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Introduction to Cell Biology

ContentsArticles

Cell (biology) 1Cell membrane 13Cytosol 20Cytoplasm 26Organelle 28Cell nucleus 34Nucleolus 48Ribosome 51Vesicle (biology and chemistry) 57Endoplasmic reticulum 62Golgi apparatus 66Cytoskeleton 70Mitochondrion 74Vacuole 91Lysosome 94Centrosome 97DNA 101Genome 119

ReferencesArticle Sources and Contributors 126Image Sources, Licenses and Contributors 133

Article LicensesLicense 136

Cell (biology) 1

Cell (biology)

Cell

Onion (Allium) cells in different phases of the cell cycle

The cells of eukaryotes (left) and prokaryotes (right)

The cell is the basic structural, functional and biological unit of all known living organisms. Cells are the smallestunit of life that can replicate independently, and are often called the "building blocks of life".Cells consist of a protoplasm enclosed within a membrane, which contains many biomolecules such as proteins andnucleic acids.[1] Organisms can be classified as unicellular (consisting of a single cell; including most bacteria) ormulticellular (including plants and animals). While the number of cells in plants and animals varies from species tospecies, humans contain about 100 trillion (1014) cells. Most plant and animal cells are visible only under themicroscope, with dimensions between 1 and 100 micrometres.The cell was discovered by Robert Hooke in 1665. The cell theory, first developed in 1839 by Matthias JakobSchleiden and Theodor Schwann, states that all organisms are composed of one or more cells, that all cells comefrom preexisting cells, that vital functions of an organism occur within cells, and that all cells contain the hereditaryinformation necessary for regulating cell functions and for transmitting information to the next generation of cells.Cells emerged on Earth at least 3.5 billion years ago.The word cell comes from the Latin cella, meaning "small room". It was coined by Robert Hooke in his bookMicrographia (1665), in which he compared the cork cells he saw through his microscope to the small rooms monkslived in.[2]

AnatomyThere are two types of cells, eukaryotes, which contain a nucleus, and prokaryotes, which do not. Prokaryotic cellsare usually single-celled organisms, while eukaryotic cells can be either single-celled or part of multicellularorganisms.

Cell (biology) 2

Table 1: Comparison of features of prokaryotic and eukaryotic cells

Prokaryotes Eukaryotes

Typical organisms bacteria, archaea protists, fungi, plants, animals

Typical size ~ 1–5 µm ~ 10–100 µm

Type of nucleus nucleoid region; no true nucleus true nucleus with double membrane

DNA circular (usually) linear molecules (chromosomes) with histone proteins

RNA/protein synthesis coupled in the cytoplasm RNA synthesis in the nucleusprotein synthesis in the cytoplasm

Ribosomes 50S and 30S 60S and 40S

Cytoplasmic structure very few structures highly structured by endomembranes and a cytoskeleton

Cell movement flagella made of flagellin flagella and cilia containing microtubules; lamellipodia and filopodia containing actin

Mitochondria none one to several thousand (though some lack mitochondria)

Chloroplasts none in algae and plants

Organization usually single cells single cells, colonies, higher multicellular organisms with specialized cells

Cell division Binary fission (simple division) Mitosis (fission or budding)Meiosis

Prokaryotic cells

Diagram of a typical prokaryotic cell

Prokaryotic cells were the first form of lifeon Earth. They are simpler and smaller thaneukaryotic cells, and lack membrane-boundorganelles such as the nucleus. Prokaryotesinclude two of the domains of life, bacteriaand archaea. The DNA of a prokaryotic cellconsists of a single chromosome that is indirect contact with the cytoplasm. Thenuclear region in the cytoplasm is called thenucleoid.

A prokaryotic cell has three architecturalregions:• On the outside, flagella and pili project

from the cell's surface. These arestructures (not present in all prokaryotes)made of proteins that facilitate movementand communication between cells.

• Enclosing the cell is the cell envelope – generally consisting of a cell wall covering a plasma membrane thoughsome bacteria also have a further covering layer called a capsule. The envelope gives rigidity to the cell andseparates the interior of the cell from its environment, serving as a protective filter. Though most prokaryoteshave a cell wall, there are exceptions such as Mycoplasma (bacteria) and Thermoplasma (archaea). The cell wallconsists of peptidoglycan in bacteria, and acts as an additional barrier against exterior forces. It also prevents thecell from expanding and bursting (cytolysis) from osmotic pressure due to a hypotonic environment. Someeukaryotic cells (plant cells and fungal cells) also have a cell wall.

Cell (biology) 3

• Inside the cell is the cytoplasmic region that contains the genome (DNA), ribosomes and various sorts ofinclusions. The prokaryotic chromosome is usually a circular molecule (an exception is that of the bacteriumBorrelia burgdorferi, which causes Lyme disease).[3] Though not forming a nucleus, the DNA is condensed in anucleoid. Prokaryotes can carry extrachromosomal DNA elements called plasmids, which are usually circular.Plasmids encode additional genes, such as antibiotic resistance genes.

Eukaryotic cellsPlants, animals, fungi, slime moulds, protozoa, and algae are all eukaryotic. These cells are about fifteen times widerthan a typical prokaryote and can be as much as a thousand times greater in volume. The main distinguishing featureof eukaryotes as compared to prokaryotes is compartmentalization: the presence of membrane-bound compartmentsin which specific metabolic activities take place. Most important among these is a cell nucleus, amembrane-delineated compartment that houses the eukaryotic cell's DNA. This nucleus gives the eukaryote itsname, which means "true nucleus." Other differences include:•• The plasma membrane resembles that of prokaryotes in function, with minor differences in the setup. Cell walls

may or may not be present.• The eukaryotic DNA is organized in one or more linear molecules, called chromosomes, which are associated

with histone proteins. All chromosomal DNA is stored in the cell nucleus, separated from the cytoplasm by amembrane. Some eukaryotic organelles such as mitochondria also contain some DNA.

• Many eukaryotic cells are ciliated with primary cilia. Primary cilia play important roles in chemosensation,mechanosensation, and thermosensation. Cilia may thus be "viewed as a sensory cellular antennae thatcoordinates a large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility oralternatively to cell division and differentiation."

• Eukaryotes can move using motile cilia or flagella. Eukaryotic flagella are less complex than those ofprokaryotes.

Structure of a typical animal cell Structure of a typical plant cell

Table 2: Comparison of structures between animal and plant cells

Typical animal cell Typical plant cell

Cell (biology) 4

Organelles •• Nucleus

• Nucleolus (within the nucleus)• Rough endoplasmic reticulum (ER)•• Smooth endoplasmic reticulum• Ribosomes•• Cytoskeleton•• Golgi apparatus•• Cytoplasm•• Mitochondria•• Vesicles• Lysosomes•• Centrosome

• Centrioles

•• Nucleus

• Nucleolus (within the nucleus)•• Rough endoplasmic reticulum•• Smooth endoplasmic reticulum•• Ribosomes•• Cytoskeleton• Golgi apparatus (dictiosomes)•• Cytoplasm•• Mitochondria• Plastids and their derivatives• Vacuole(s)•• Cell wall

Subcellular components

Illustration depicting major structures inside aneukaryotic animal cell

All cells, whether prokaryotic or eukaryotic, have a membrane thatenvelops the cell, separates its interior from its environment, regulateswhat moves in and out (selectively permeable), and maintains theelectric potential of the cell. Inside the membrane, a salty cytoplasmtakes up most of the cell volume. All cells (except red blood cellswhich lack a cell nucleus and most organelles to accommodatemaximum space for hemoglobin) possess DNA, the hereditary materialof genes, and RNA, containing the information necessary to buildvarious proteins such as enzymes, the cell's primary machinery. Thereare also other kinds of biomolecules in cells. This article lists theseprimary components of the cell, then briefly describes their function.

Membrane

The cell membrane, or plasma membrane, surrounds the cytoplasm ofa cell. In animals, the plasma membrane is the outer boundary of the cell, while in plants and prokaryotes it isusually covered by a cell wall. This membrane serves to separate and protect a cell from its surrounding environmentand is made mostly from a double layer of phospholipids, which are amphiphilic (partly hydrophobic and partlyhydrophilic). Hence, the layer is called a phospholipid bilayer, or sometimes a fluid mosaic membrane. Embeddedwithin this membrane is a variety of protein molecules that act as channels and pumps that move different moleculesinto and out of the cell. The membrane is said to be 'semi-permeable', in that it can either let a substance (molecule orion) pass through freely, pass through to a limited extent or not pass through at all. Cell surface membranes alsocontain receptor proteins that allow cells to detect external signaling molecules such as hormones.

Cell (biology) 5

Cytoskeleton

A fluorescent image of an endothelial cell. Nuclei are stained blue,mitochondria are stained red, and microfilaments are stained green.

The cytoskeleton acts to organize and maintain thecell's shape; anchors organelles in place; helps duringendocytosis, the uptake of external materials by a cell,and cytokinesis, the separation of daughter cells aftercell division; and moves parts of the cell in processes ofgrowth and mobility. The eukaryotic cytoskeleton iscomposed of microfilaments, intermediate filamentsand microtubules. There are a great number of proteinsassociated with them, each controlling a cell's structureby directing, bundling, and aligning filaments. Theprokaryotic cytoskeleton is less well-studied but isinvolved in the maintenance of cell shape, polarity andcytokinesis.

Genetic material

Two different kinds of genetic material exist: deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Most cellsuse DNA for their long-term information storage. The biological information contained in an organism is encoded inits DNA sequence. RNA is used for information transport (e.g., mRNA) and enzymatic functions (e.g., ribosomalRNA). Transfer RNA (tRNA) molecules are used to add amino acids during protein translation.

Prokaryotic genetic material is organized in a simple circular DNA molecule (the bacterial chromosome) in thenucleoid region of the cytoplasm. Eukaryotic genetic material is divided into different, linear molecules calledchromosomes inside a discrete nucleus, usually with additional genetic material in some organelles like mitochondriaand chloroplasts (see endosymbiotic theory).A human cell has genetic material contained in the cell nucleus (the nuclear genome) and in the mitochondria (themitochondrial genome). In humans the nuclear genome is divided into 46 linear DNA molecules calledchromosomes, including 22 homologous chromosome pairs and a pair of sex chromosomes. The mitochondrialgenome is a circular DNA molecule distinct from the nuclear DNA. Although the mitochondrial DNA is very smallcompared to nuclear chromosomes, it codes for 13 proteins involved in mitochondrial energy production and specifictRNAs.Foreign genetic material (most commonly DNA) can also be artificially introduced into the cell by a process calledtransfection. This can be transient, if the DNA is not inserted into the cell's genome, or stable, if it is. Certain virusesalso insert their genetic material into the genome.

OrganellesOrganelles are parts of the cell which are adapted and/or specialized for carrying out one or more vital functions,analogous to the organs of the human body (such as the heart, lung, and kidney, with each organ performing adifferent function). Both eukaryotic and prokaryotic cells have organelles, but prokaryotic organelles are generallysimpler and are not membrane-bound.There are several types of organelles in a cell. Some (such as the nucleus and golgi apparatus) are typically solitary,while others (such as mitochondria, chloroplasts, peroxisomes and lysosomes) can be numerous (hundreds tothousands). The cytosol is the gelatinous fluid that fills the cell and surrounds the organelles.

Cell (biology) 6

Eukaryotic

• Cell nucleus: A cell's information center, the cell nucleus is the most conspicuous organelle found in a eukaryoticcell. It houses the cell's chromosomes, and is the place where almost all DNA replication and RNA synthesis(transcription) occur. The nucleus is spherical and separated from the cytoplasm by a double membrane called thenuclear envelope. The nuclear envelope isolates and protects a cell's DNA from various molecules that couldaccidentally damage its structure or interfere with its processing. During processing, DNA is transcribed, orcopied into a special RNA, called messenger RNA (mRNA). This mRNA is then transported out of the nucleus,where it is translated into a specific protein molecule. The nucleolus is a specialized region within the nucleuswhere ribosome subunits are assembled. In prokaryotes, DNA processing takes place in the cytoplasm.

• Mitochondria and Chloroplasts: the power generators: Mitochondria are self-replicating organelles that occur invarious numbers, shapes, and sizes in the cytoplasm of all eukaryotic cells. Mitochondria play a critical role ingenerating energy in the eukaryotic cell. Respiration occurs in the cell mitochondria, which generate the cell'senergy by oxidative phosphorylation, using oxygen to release energy stored in cellular nutrients (typicallypertaining to glucose) to generate ATP. Mitochondria multiply by binary fission, like prokaryotes. Chloroplastscan only be found in plants and algae, and they capture the sun's energy to make ATP.

Diagram of an endomembrane system

• Endoplasmic reticulum: The endoplasmic reticulum (ER) is atransport network for molecules targeted for certain modificationsand specific destinations, as compared to molecules that float freelyin the cytoplasm. The ER has two forms: the rough ER, which hasribosomes on its surface that secrete proteins into the ER, and thesmooth ER, which lacks ribosomes. The smooth ER plays a role incalcium sequestration and release. (See Endoplasmic reticulum)

• Golgi apparatus: The primary function of the Golgi apparatus is toprocess and package the macromolecules such as proteins and lipidsthat are synthesized by the cell. (See Golgi apparatus)

• Lysosomes and Peroxisomes: Lysosomes contain digestiveenzymes (acid hydrolases). They digest excess or worn-outorganelles, food particles, and engulfed viruses or bacteria.Peroxisomes have enzymes that rid the cell of toxic peroxides. Thecell could not house these destructive enzymes if they were not contained in a membrane-bound system. (SeeLysosome and Peroxisome)

• Centrosome – the cytoskeleton organiser: The centrosome produces the microtubules of a cell – a keycomponent of the cytoskeleton. It directs the transport through the ER and the Golgi apparatus. Centrosomes arecomposed of two centrioles, which separate during cell division and help in the formation of the mitotic spindle.A single centrosome is present in the animal cells. They are also found in some fungi and algae cells. (SeeCentrosome)

• Vacuoles: Vacuoles store food and waste. Some vacuoles store extra water. They are often described as liquidfilled space and are surrounded by a membrane. Some cells, most notably Amoeba, have contractile vacuoles,which can pump water out of the cell if there is too much water. The vacuoles of eukaryotic cells are usuallylarger in those of plants than animals. (See Vacuole)

Cell (biology) 7

Eukaryotic and prokaryotic

• Ribosomes: The ribosome is a large complex of RNA and protein molecules. They each consist of two subunits,and act as an assembly line where RNA from the nucleus is used to synthesise proteins from amino acids.Ribosomes can be found either floating freely or bound to a membrane (the rough endoplasmatic reticulum ineukaryotes, or the cell membrane in prokaryotes).

Structures outside the cell membraneMany cells also have structures which exist wholly or partially outside the cell membrane. These structures arenotable because they are not protected from the external environment by the impermeable cell membrane. In order toassemble these structures, their components must be carried across the cell membrane by export processes.

Cell wallMany types of prokaryotic and eukaryotic cells have a cell wall. The cell wall acts to protect the cell mechanicallyand chemically from its environment, and is an additional layer of protection to the cell membrane. Different typesof cell have cell walls made up of different materials; plant cell walls are primarily made up of pectin, fungi cellwalls are made up of chitin and bacteria cell walls are made up of peptidoglycan.

Prokaryotic

Capsule

A gelatinous capsule is present in some bacteria outside the cell membrane and cell wall. The capsule may bepolysaccharide as in pneumococci, meningococci or polypeptide as Bacillus anthracis or hyaluronic acid as instreptococci. (See Bacterial capsule.) Capsules are not marked by normal staining protocols and can be detected byIndia ink or Methyl blue; which allows for higher contrast between the cells for observation.:87

Flagella

Flagella are organelles for cellular mobility. The bacterial flagellum stretches from cytoplasm through the cellmembrane(s) and extrudes through the cell wall. They are long and thick thread-like appendages, protein in nature.Are most commonly found in bacteria cells but are found in animal cells as well.

Fimbriae (pili)

They are short and thin hair-like filaments, formed of protein called pilin (antigenic). Fimbriae are responsible forattachment of bacteria to specific receptors of human cell (adherence). There are special types of pili called (sex pili)involved in conjunction. (See Pilus.)

Growth and metabolismBetween successive cell divisions, cells grow through the functioning of cellular metabolism. Cell metabolism is theprocess by which individual cells process nutrient molecules. Metabolism has two distinct divisions: catabolism, inwhich the cell breaks down complex molecules to produce energy and reducing power, and anabolism, in which thecell uses energy and reducing power to construct complex molecules and perform other biological functions.Complex sugars consumed by the organism can be broken down into a less chemically complex sugar moleculecalled glucose. Once inside the cell, glucose is broken down to make adenosine triphosphate (ATP), a form ofenergy, through two different pathways.The first pathway, glycolysis, requires no oxygen and is referred to as anaerobic metabolism. Each reaction producesATP and NADH, which are used in cellular functions, as well as two pyruvate molecules that derive from theoriginal glucose molecule. In prokaryotes, all energy is produced by glycolysis.

Cell (biology) 8

The second pathway, called the Krebs cycle or citric acid cycle, is performed only by eukaryotes and involves furtherbreakdown of the pyruvate produced in glycolysis. It occurs inside the mitochondria and generates much moreenergy than glycolysis, mostly through oxidative phosphorylation.

Replication

Bacteria divide by binary fission, while eukaryotes divide by mitosisor meiosis.

Cell division involves a single cell (called a mothercell) dividing into two daughter cells. This leads togrowth in multicellular organisms (the growth oftissue) and to procreation (vegetative reproduction) inunicellular organisms. Prokaryotic cells divide bybinary fission, while eukaryotic cells usually undergo aprocess of nuclear division, called mitosis, followed bydivision of the cell, called cytokinesis. A diploid cellmay also undergo meiosis to produce haploid cells,usually four. Haploid cells serve as gametes inmulticellular organisms, fusing to form new diploidcells.

DNA replication, or the process of duplicating a cell'sgenome, always happens when a cell divides throughmitosis or binary fission. This occurs during the Sphase of the cell cycle.

In meiosis, the DNA is replicated only once, while thecell divides twice. DNA replication only occurs before

meiosis I. DNA replication does not occur when the cells divide the second time, in meiosis II. Replication, like allcellular activities, requires specialized proteins for carrying out the job.

Cell (biology) 9

Protein synthesis

An overview of proteinsynthesis.Within the

nucleus of the cell (lightblue), genes (DNA, darkblue) are transcribed intoRNA. This RNA is then

subject topost-transcriptional

modification and control,resulting in a mature

mRNA (red) that is thentransported out of thenucleus and into the

cytoplasm (peach), whereit undergoes translationinto a protein. mRNA istranslated by ribosomes(purple) that match the

three-base codons of themRNA to the three-base

anti-codons of theappropriate tRNA. Newly

synthesized proteins(black) are often further

modified, such as bybinding to an effectormolecule (orange), tobecome fully active.

Cells are capable of synthesizing new proteins, which are essential for the modulationand maintenance of cellular activities. This process involves the formation of newprotein molecules from amino acid building blocks based on information encoded inDNA/RNA. Protein synthesis generally consists of two major steps: transcription andtranslation.

Transcription is the process where genetic information in DNA is used to produce acomplementary RNA strand. This RNA strand is then processed to give messenger RNA(mRNA), which is free to migrate through the cell. mRNA molecules bind toprotein-RNA complexes called ribosomes located in the cytosol, where they aretranslated into polypeptide sequences. The ribosome mediates the formation of apolypeptide sequence based on the mRNA sequence. The mRNA sequence directlyrelates to the polypeptide sequence by binding to transfer RNA (tRNA) adaptermolecules in binding pockets within the ribosome. The new polypeptide then folds into afunctional three-dimensional protein molecule.

Movement or motility

Cells can move during many processes: such as wound healing, the immune responseand cancer metastasis. For wound healing to occur, white blood cells and cells that ingestbacteria move to the wound site to kill the microorganisms that cause infection.At the same time fibroblasts (connective tissue cells) move there to remodel damagedstructures. In the case of tumor development, cells from a primary tumor move away andspread to other parts of the body. Cell motility involves many receptors, crosslinking,bundling, binding, adhesion, motor and other proteins. The process is divided into threesteps – protrusion of the leading edge of the cell, adhesion of the leading edge andde-adhesion at the cell body and rear, and cytoskeletal contraction to pull the cellforward. Each step is driven by physical forces generated by unique segments of thecytoskeleton.[4][5]

Origins

The origin of cells has to do with the origin of life, which began the history of life onEarth.

Cell (biology) 10

Origin of the first cell

Stromatolites are left behind by cyanobacteria, also called blue-greenalgae. They are the oldest known fossils of life on Earth. Thisone-billion-year-old fossil is from Glacier National Park in the

United States.

There are several theories about the origin of smallmolecules that led to life on the early Earth. They mayhave been carried to Earth on meteorites (seeMurchison meteorite), created at deep-sea vents, orsynthesized by lightning in a reducing atmosphere (seeMiller–Urey experiment). There is little experimentaldata defining what the first self-replicating forms were.RNA is thought to be the earliest self-replicatingmolecule, as it is capable of both storing geneticinformation and catalyzing chemical reactions (seeRNA world hypothesis), but some other entity with thepotential to self-replicate could have preceded RNA,such as clay or peptide nucleic acid.

Cells emerged at least 3.5 billion years ago.[][] Thecurrent belief is that these cells were heterotrophs. Theearly cell membranes were probably more simple and permeable than modern ones, with only a single fatty acidchain per lipid. Lipids are known to spontaneously form bilayered vesicles in water, and could have preceded RNA,but the first cell membranes could also have been produced by catalytic RNA, or even have required structuralproteins before they could form.

Origin of eukaryotic cellsThe eukaryotic cell seems to have evolved from a symbiotic community of prokaryotic cells. DNA-bearingorganelles like the mitochondria and the chloroplasts are descended from ancient symbiotic oxygen-breathingproteobacteria and cyanobacteria, respectively, which were endosymbiosed by an ancestral archaean prokaryote.There is still considerable debate about whether organelles like the hydrogenosome predated the origin ofmitochondria, or vice versa: see the hydrogen hypothesis for the origin of eukaryotic cells.Sex, as the stereotyped choreography of meiosis and syngamy that persists in nearly all extant eukaryotes, may haveplayed a role in the transition from prokaryotes to eukaryotes. One view, on the origin of sex in eukaryotic cells, isthat eukaryotic sex evolved from a prokaryotic sexual process termed transformation. According to this view,bacterial transformation is an adaptation for repairing DNA damages that arise during stressful conditions, and thisrole has been maintained in meiosis, where recombinational DNA repair is promoted. Thus the adaptive benefit ofprokaryotic sex, recombinational repair, was maintained through the evolutionary transition from prokaryotes tosingle-celled eukaryotes.[6][7] This view is also presented in the Wikipedia articles Transformation (genetics),Evolution of sexual reproduction and Sex.In another view, an 'origin of sex as vaccination' theory suggests that the eukaryote genome accreted from prokaryanparasite genomes in numerous rounds of lateral gene transfer. Sex-as-syngamy (fusion sex) arose when infectedhosts began swapping nuclearized genomes containing co-evolved, vertically transmitted symbionts that conveyedprotection against horizontal infection by more virulent symbionts.

Cell (biology) 11

History of research• 1632–1723: Antonie van Leeuwenhoek teaches himself to make lenses, constructs simple microscopes and draws

protozoa, such as Vorticella from rain water, and bacteria from his own mouth.• 1665: Robert Hooke discovers cells in cork, then in living plant tissue using an early compound microscope.• 1839: Theodor Schwann and Matthias Jakob Schleiden elucidate the principle that plants and animals are made of

cells, concluding that cells are a common unit of structure and development, and thus founding the cell theory.• 1855: Rudolf Virchow states that new cells come from pre-existing cells by cell division (omnis cellula ex

cellula).• 1859: The belief that life forms can occur spontaneously (generatio spontanea) is contradicted by Louis Pasteur

(1822–1895) (although Francesco Redi had performed an experiment in 1668 that suggested the sameconclusion).

• 1931: Ernst Ruska builds the first transmission electron microscope (TEM) at the University of Berlin. By 1935,he has built an EM with twice the resolution of a light microscope, revealing previously unresolvable organelles.

• 1953: Watson and Crick made their first announcement on the double helix structure of DNA on February 28.• 1981: Lynn Margulis published Symbiosis in Cell Evolution detailing the endosymbiotic theory.

References[1] Cell Movements and the Shaping of the Vertebrate Body (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Search& db=books&

doptcmdl=GenBookHL& term=Cell+ Movements+ and+ the+ Shaping+ of+ the+ Vertebrate+ Body+ AND+ mboc4[book]+ AND+374635[uid]& rid=mboc4. section. 3919) in Chapter 21 of Molecular Biology of the Cell (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query.fcgi?cmd=Search& db=books& doptcmdl=GenBookHL& term=cell+ biology+ AND+ mboc4[book]+ AND+ 373693[uid]& rid=mboc4)fourth edition, edited by Bruce Alberts (2002) published by Garland Science.The Alberts text discusses how the "cellular building blocks" move to shape developing embryos. It is also common to describe smallmolecules such as amino acids as " molecular building blocks (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Search&db=books& doptcmdl=GenBookHL& term="all+ cells"+ AND+ mboc4[book]+ AND+ 372023[uid]& rid=mboc4. section. 4#23)".

[2] "... I could exceedingly plainly perceive it to be all perforated and porous, much like a Honey-comb, but that the pores of it were not regular[..] these pores, or cells, [..] were indeed the first microscopical pores I ever saw, and perhaps, that were ever seen, for I had not met with anyWriter or Person, that had made any mention of them before this. . ." – Hooke describing his observations on a thin slice of cork. RobertHooke (http:/ / www. ucmp. berkeley. edu/ history/ hooke. html)

[3] European Bioinformatics Institute, Karyn's Genomes: Borrelia burgdorferi (http:/ / www. ebi. ac. uk/ 2can/ genomes/ bacteria/Borrelia_burgdorferi. html), part of 2can on the EBI-EMBL database. Retrieved 5 August 2012

[4][4] Alberts B, Johnson A, Lewis J. et al. Molecular Biology of the Cell, 4e. Garland Science. 2002[5] Ananthakrishnan R, Ehrlicher A. The Forces Behind Cell Movement. Int J Biol Sci 2007; 3:303–317. http:/ / www. biolsci. org/ v03p0303.

htm[6] Bernstein H, Bernstein C. (2010) Evolutionary Origin of Recombination during Meiosis. BioScience 60(7):498-505. doi: http:/ / dx. doi. org/

10. 1525/ bio. 2010. 60. 7. 5[7] Bernstein H, Bernstein C, Michod RE (2012). DNA repair as the primary adaptive function of sex in bacteria and eukaryotes. Chapter 1:

pp.1-49 in: DNA Repair: New Research, Sakura Kimura and Sora Shimizu editors. Nova Sci. Publ., Hauppauge, N.Y. ISBN978-1-62100-808-8 https:/ / www. novapublishers. com/ catalog/ product_info. php?products_id=31918

•  This article incorporates public domain material from the NCBI document "Science Primer" (http:/ / www.ncbi. nlm. nih. gov/ About/ primer/ index. html).

Cell (biology) 12

External links• Inside the Cell (http:/ / publications. nigms. nih. gov/ insidethecell/ ) - a science education booklet by National

Institutes of Health, in PDF and ePub.• Cells Alive! (http:/ / www. cellsalive. com/ )• Cell Biology (http:/ / www. biology. arizona. edu/ cell_bio/ cell_bio. html) in "The Biology Project" of University

of Arizona.• Centre of the Cell online (http:/ / www. centreofthecell. org/ )• The Image & Video Library of The American Society for Cell Biology (http:/ / cellimages. ascb. org/ ), a

collection of peer-reviewed still images, video clips and digital books that illustrate the structure, function andbiology of the cell.

• HighMag Blog (http:/ / highmagblog. blogspot. com/ ), still images of cells from recent research articles.• New Microscope Produces Dazzling 3D Movies of Live Cells (http:/ / www. hhmi. org/ news/ betzig20110304.

html), March 4, 2011 - Howard Hughes Medical Institute.• WormWeb.org: Interactive Visualization of the C. elegans Cell lineage (http:/ / wormweb. org/ celllineage) -

Visualize the entire cell lineage tree of the nematode C. elegans

Textbooks• Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular Biology of the Cell (http:/ / www.

ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=mboc4. TOC& depth=2) (4th ed.). Garland. ISBN 0-8153-3218-1.• Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipurksy SL, Darnell J (2004). Molecular

Cell Biology (http:/ / www. ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=mcb. TOC) (5th ed.). WH Freeman: NewYork, NY. ISBN 978-0-7167-4366-8.

• Cooper GM (2000). The cell: a molecular approach (http:/ / www. ncbi. nlm. nih. gov/ books/ bv.fcgi?rid=cooper. TOC& depth=2) (2nd ed.). Washington, D.C: ASM Press. ISBN 0-87893-102-3.

Cell membrane 13

Cell membrane

Illustration of a Eukaryotic cell membrane

The 'cell membrane' (also known as theplasma membrane or cytoplasmicmembrane) is a biological membranethat separates the interior of all cells fromthe outside environment.[1] The cellmembrane is selectively permeable toions and organic molecules and controlsthe movement of substances in and out ofcells. The basic function of the cellmembrane is to protect the cell from itssurroundings. It consists of thephospholipid bilayer with embeddedproteins. Cell membranes are involved ina variety of cellular processes such as celladhesion, ion conductivity and cellsignaling and serve as the attachmentsurface for several extracellularstructures, including the cell wall,glycocalyx, and intracellularcytoskeleton. Cell membranes can beartificially reassembled.

Function

A detailed diagram of the cell membrane

The cell membrane or plasmamembrane surrounds the cytoplasm ofliving cells, physically separating theintracellular components from theextracellular environment. Fungi,bacteria and plants also have the cellwall which provides a mechanicalsupport for the cell and precludes thepassage of larger molecules. The cellmembrane also plays a role inanchoring the cytoskeleton provideshape to the cell, and in attaching to the extracellular matrix and other cells to help group cells together to formtissues.

Cell membrane 14

Illustration depicting cellular diffusion

The membrane is selectively permeable and able to regulate whatenters and exits the cell, thus facilitating the transport of materialsneeded for survival. The movement of substances across the membranecan be either "passive", occurring without the input of cellular energy,or active, requiring the cell to expend energy in transporting it. Themembrane also maintains the cell potential. The cell membrane thusworks as a selective filter that allows only certain things to come insideor go outside the cell. The cell employs a number of transportmechanisms that involve biological membranes:

1. Passive osmosis and diffusion: Some substances (small molecules, ions) such as carbon dioxide (CO2) and oxygen(O2), can move across the plasma membrane by diffusion, which is a passive transport process. Because themembrane acts as a barrier for certain molecules and ions, they can occur in different concentrations on the two sidesof the membrane. Such a concentration gradient across a semipermeable membrane sets up an osmotic flow for thewater.2. Transmembrane protein channels and transporters: Nutrients, such as sugars or amino acids, must enter the cell,and certain products of metabolism must leave the cell. Such molecules are pumped across the membrane bytransmembrane transporters or diffuse through protein channels such as Aquaporins (in the case of water (H2O)).These proteins, also called permeases, are usually quite specific, recognizing and transporting only a limited foodgroup of chemical substances, often even only a single substance.3. Endocytosis: Endocytosis is the process in which cells absorb molecules by engulfing them. The plasmamembrane creates a small deformation inward, called an invagination, in which the substance to be transported iscaptured. The deformation then pinches off from the membrane on the inside of the cell, creating a vesiclecontaining the captured substance. Endocytosis is a pathway for internalizing solid particles (cell eating orphagocytosis), small molecules and ions (cell drinking or pinocytosis), and macromolecules. Endocytosis requiresenergy and is thus a form of active transport.4. Exocytosis: Just as material can be brought into the cell by invagination and formation of a vesicle, the membraneof a vesicle can be fused with the plasma membrane, extruding its contents to the surrounding medium. This is theprocess of exocytosis. Exocytosis occurs in various cells to remove undigested residues of substances brought in byendocytosis, to secrete substances such as hormones and enzymes, and to transport a substance completely across acellular barrier. In the process of exocytosis, the undigested waste-containing food vacuole or the secretory vesiclebudded from Golgi apparatus, is first moved by cytoskeleton from the interior of the cell to the surface. The vesiclemembrane comes in contact with the plasma membrane. The lipid molecules of the two bilayers rearrangethemselves and the two membranes are, thus, fused. A passage is formed in the fused membrane and the vesiclesdischarges its contents outside the cell.

Cell membrane 15

ProkaryotesGram-negative bacteria have both a plasma membrane and an outer membrane separated by a periplasmic space.Other prokaryotes have only a plasma membrane. Prokaryotic cells are also surrounded by a cell wall composed ofpeptidoglycan (amino acids and sugars). Some eukaryotic cells also have cells walls, but none that are made ofpeptidoglycan.

Structures

Fluid mosaic modelAccording to the fluid mosaic model of S.J.Singer and G.L. Nicolson (1972), which replaced the earlier model ofDavson and Danielli, biological membranes can be considered as a two-dimensional liquid in which lipid and proteinmolecules diffuse more or less easily. Although the lipid bilayers that form the basis of the membranes do indeedform two-dimensional liquids by themselves, the plasma membrane also contains a large quantity of proteins, whichprovide more structure. Examples of such structures are protein-protein complexes, pickets and fences formed by theactin-based cytoskeleton, and potentially lipid rafts.

Lipid bilayer

Diagram of the arrangement of amphipathic lipidmolecules to form a lipid bilayer. The yellow polar

head groups separate the grey hydrophobic tails fromthe aqueous cytosolic and extracellular environments.

Lipid bilayers form through the process of self-assembly. The cellmembrane consists primarily of a thin layer of amphipathicphospholipids which spontaneously arrange so that thehydrophobic "tail" regions are isolated from the surrounding polarfluid, causing the more hydrophilic "head" regions to associatewith the intracellular (cytosolic) and extracellular faces of theresulting bilayer. This forms a continuous, spherical lipid bilayer.Forces such as van der Waals, electrostatic, hydrogen bonds, andnoncovalent interactions all contribute to the formation of the lipidbilayer. Overall, hydrophobic interactions are the major drivingforce in the formation of lipid bilayers.

Lipid bilayers are generally impermeable to ions and polar molecules. The arrangement of hydrophilic heads andhydrophobic tails of the lipid bilayer prevent polar solutes (ex. amino acids, nucleic acids, carbohydrates, proteins,and ions) from diffusing across the membrane, but generally allows for the passive diffusion of hydrophobicmolecules. This affords the cell the ability to control the movement of these substances via transmembrane proteincomplexes such as pores, channels and gates.

Flippases and scramblases concentrate phosphatidyl serine, which carries a negative charge, on the inner membrane.Along with NANA, this creates an extra barrier to charged moieties moving through the membrane.Membranes serve diverse functions in eukaryotic and prokaryotic cells. One important role is to regulate themovement of materials into and out of cells. The phospholipid bilayer structure (fluid mosaic model) with specificmembrane proteins accounts for the selective permeability of the membrane and passive and active transportmechanisms. In addition, membranes in prokaryotes and in the mitochondria and chloroplasts of eukaryotes facilitatethe synthesis of ATP through chemiosmosis.

Cell membrane 16

Membrane polarity

Alpha intercalated cell

The apical membrane of a polarized cell isthe surface of the plasma membrane thatfaces inward to the lumen. This isparticularly evident in epithelial andendothelial cells, but also describes otherpolarized cells, such as neurons. Thebasolateral membrane of a polarized cell isthe surface of the plasma membrane thatforms its basal and lateral surfaces. It facesoutwards, towards the interstitium, andaway from the lumen. Basolateralmembrane is a compound phrase referring tothe terms "basal (base) membrane" and"lateral (side) membrane", which, especiallyin epithelial cells, are identical incomposition and activity. Proteins (such asion channels and pumps) are free to move from the basal to the lateral surface of the cell or vice versa in accordancewith the fluid mosaic model. Tight junctions join epithelial cells near their apical surface to prevent the migration ofproteins from the basolateral membrane to the apical membrane. The basal and lateral surfaces thus remain roughlyequivalentWikipedia:Please clarify to one another, yet distinct from the apical surface.

Membrane structuresCell membrane can form different types of "supramembrane" structures such as caveola, postsynaptic density,podosome, invadopodium, focal adhesion, and different types of cell junctions. These structures are usuallyresponsible for cell adhesion, communication, endocytosis and exocytosis. They can be visualized by electronmicroscopy or fluorescence microscopy. They are composed of specific proteins, such as integrins and cadherins.

CytoskeletonThe cytoskeleton is found underlying the cell membrane in the cytoplasm and provides a scaffolding for membraneproteins to anchor to, as well as forming organelles that extend from the cell. Indeed, cytoskeletal elements interactextensively and intimately with the cell membrane. Anchoring proteins restricts them to a particular cell surface —for example, the apical surface of epithelial cells that line the vertebrate gut — and limits how far they may diffusewithin the bilayer. The cytoskeleton is able to form appendage-like organelles, such as cilia, which aremicrotubule-based extensions covered by the cell membrane, and filopodia, which are actin-based extensions. Theseextensions are ensheathed in membrane and project from the surface of the cell in order to sense the externalenvironment and/or make contact with the substrate or other cells. The apical surfaces of epithelial cells are densewith actin-based finger-like projections known as microvilli, which increase cell surface area and thereby increasethe absorption rate of nutrients. Localized decoupling of the cytoskeleton and cell membrane results in formation ofa bleb.

Cell membrane 17

CompositionCell membranes contain a variety of biological molecules, notably lipids and proteins. Material is incorporated intothe membrane, or deleted from it, by a variety of mechanisms:• Fusion of intracellular vesicles with the membrane (exocytosis) not only excretes the contents of the vesicle but

also incorporates the vesicle membrane's components into the cell membrane. The membrane may form blebsaround extracellular material that pinch off to become vesicles (endocytosis).

•• If a membrane is continuous with a tubular structure made of membrane material, then material from the tube canbe drawn into the membrane continuously.

•• Although the concentration of membrane components in the aqueous phase is low (stable membrane componentshave low solubility in water), there is an exchange of molecules between the lipid and aqueous phases.

Lipids

Examples of the major membrane phospholipids and glycolipids: phosphatidylcholine(PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns),

phosphatidylserine (PtdSer).

The cell membrane consists of threeclasses of amphipathic lipids:phospholipids, glycolipids, and sterols.The amount of each depends upon thetype of cell, but in the majority of casesphospholipids are the most abundant. InRBC studies, 30% of the plasmamembrane is lipid.

The fatty chains in phospholipids andglycolipids usually contain an evennumber of carbon atoms, typicallybetween 16 and 20. The 16- and18-carbon fatty acids are the mostcommon. Fatty acids may be saturated orunsaturated, with the configuration of thedouble bonds nearly always "cis". Thelength and the degree of unsaturation offatty acid chains have a profound effecton membrane fluidity as unsaturatedlipids create a kink, preventing the fattyacids from packing together as tightly,thus decreasing the melting temperature(increasing the fluidity) of the membrane.The ability of some organisms to regulate the fluidity of their cell membranes by altering lipid composition is calledhomeoviscous adaptation.

The entire membrane is held together via non-covalent interaction of hydrophobic tails, however the structure isquite fluid and not fixed rigidly in place. Under physiological conditions phospholipid molecules in the cellmembrane are in the liquid crystalline state. It means the lipid molecules are free to diffuse and exhibit rapid lateraldiffusion along the layer in which they are present. However, the exchange of phospholipid molecules betweenintracellular and extracellular leaflets of the bilayer is a very slow process. Lipid rafts and caveolae are examples ofcholesterol-enriched microdomains in the cell membrane.

In animal cells cholesterol is normally found dispersed in varying degrees throughout cell membranes, in theirregular spaces between the hydrophobic tails of the membrane lipids, where it confers a stiffening and

Cell membrane 18

strengthening effect on the membrane.

Phospholipids forming lipid vesiclesLipid vesicles or liposomes are circular pockets that are enclosed by a lipid bilayer. These structures are used inlaboratories to study the effects of chemicals in cells by delivering these chemicals directly to the cell, as well asgetting more insight into cell membrane permeability. Lipid vesicles and liposomes are formed by first suspending alipid in an aqueous solution then agitating the mixture through sonication, resulting in a vesicle. By measuring therate of efflux from that of the inside of the vesicle to the ambient solution, allows researcher to better understandmembrane permeability. Vesicles can be formed with molecules and ions inside the vesicle by forming the vesiclewith the desired molecule or ion present in the solution. Proteins can also be embedded into the membrane throughsolubilizing the desired proteins in the presence of detergents and attaching them to the phospholipids in which theliposome is formed. These provide researchers with a tool to examine various membrane protein functions.

CarbohydratesPlasma membranes also contain carbohydrates, predominantly glycoproteins, but with some glycolipids(cerebrosides and gangliosides). For the most part, no glycosylation occurs on membranes within the cell; rathergenerally glycosylation occurs on the extracellular surface of the plasma membrane. The glycocalyx is an importantfeature in all cells, especially epithelia with microvilli. Recent data suggest the glycocalyx participates in celladhesion, lymphocyte homing, and many others. The penultimate sugar is galactose and the terminal sugar is sialicacid, as the sugar backbone is modified in the golgi apparatus. Sialic acid carries a negative charge, providing anexternal barrier to charged particles.

Proteins

Type Description Examples

Integral proteinsortransmembraneproteins

Span the membrane and have a hydrophilic cytosolic domain, which interacts with internalmolecules, a hydrophobic membrane-spanning domain that anchors it within the cellmembrane, and a hydrophilic extracellular domain that interacts with external molecules. Thehydrophobic domain consists of one, multiple, or a combination of α-helices and β sheetprotein motifs.

Ion channels, protonpumps, Gprotein-coupledreceptor

Lipid anchoredproteins

Covalently bound to single or multiple lipid molecules; hydrophobically insert into the cellmembrane and anchor the protein. The protein itself is not in contact with the membrane.

G proteins

Peripheralproteins

Attached to integral membrane proteins, or associated with peripheral regions of the lipidbilayer. These proteins tend to have only temporary interactions with biological membranes,and once reacted, the molecule dissociates to carry on its work in the cytoplasm.

Some enzymes, somehormones

The cell membrane has large content of proteins, typically around 50% of membrane volume These proteins areimportant for cell because they are responsible for various biological activities. Approximately a third of the genes inyeast code specifically for them, and this number is even higher in multicellular organisms.The cell membrane, being exposed to the outside environment, is an important site of cell–cell communication. Assuch, a large variety of protein receptors and identification proteins, such as antigens, are present on the surface ofthe membrane. Functions of membrane proteins can also include cell–cell contact, surface recognition, cytoskeletoncontact, signaling, enzymatic activity, or transporting substances across the membrane.Most membrane proteins must be inserted in some way into the membrane. For this to occur, an N-terminus "signalsequence" of amino acids directs proteins to the endoplasmic reticulum, which inserts the proteins into a lipidbilayer. Once inserted, the proteins are then transported to their final destination in vesicles, where the vesicle fuseswith the target membrane.

Cell membrane 19

VariationThe cell membrane has different lipid and protein compositions in distinct types of cells and may have thereforespecific names for certain cell types:• Sarcolemma in myocytes• Oolemma in oocytes• Axolemma in neuronal processes - axons•• Historically, the plasma membrane was also referred to as the plasmalemma

PermeabilityThe permeability of a membrane is the rate of passive diffusion of molecules through the membrane. Thesemolecules are known as permeant molecules. Permeability depends mainly on the electric charge and polarity of themolecule and to a lesser extent the molar mass of the molecule. Due to the cell membrane's hydrophobic nature,small electrically neutral molecules pass through the membrane more easily than charged, large ones. The inabilityof charged molecules to pass through the cell membrane results in pH partition of substances throughout the fluidcompartments of the body.

Notes and references[1] Kimball's Biology pages (http:/ / users. rcn. com/ jkimball. ma. ultranet/ BiologyPages/ C/ CellMembranes. html), Cell Membranes

External links• Lipids, Membranes and Vesicle Trafficking - The Virtual Library of Biochemistry and Cell Biology (http:/ /

www. biochemweb. org/ lipids_membranes. shtml)• Cell membrane protein extraction protocol (http:/ / www. westernblotting. org/ protocol membrane extraction.

htm)• Membrane homeostasis, tension regulation, mechanosensitive membrane exchange and membrane traffic (http:/ /

www. phys. unsw. edu. au/ ~jw/ tension. html)• 3D structures of proteins associated with plasma membrane of eukaryotic cells (http:/ / opm. phar. umich. edu/

localization. php?localization=Eukaryotic plasma membrane)• Lipid composition and proteins of some eukariotic membranes (http:/ / opm. phar. umich. edu/ atlas.

php?membrane=Eukaryotic plasma membrane)• (http:/ / www. etap. org/ demo/ biology1/ instruction3tutor. html)

Library resources

About Cell membrane

• Resources in your library (http:/ / tools. wmflabs. org/ ftl/ cgi-bin/ ftl?st=wp& su=Cell+ membrane)

Cytosol 20

Cytosol

The cytosol is a crowded solution of many different types of molecules that fillsmuch of the volume of cells.

Cell biologyThe animal cell

Components of a typical animal cell:

1.1. Nucleolus2.2. Nucleus3. Ribosome (little dots)4.4. Vesicle5.5. Rough endoplasmic reticulum6. Golgi apparatus (or "Golgi body")7.7. Cytoskeleton8.8. Smooth endoplasmic reticulum9.9. Mitochondrion10.10. Vacuole11. Cytosol (fluid that contains organelles)12.12. Lysosome13.13. Centrosome14.14. Cell membrane

Cytosol 21

The cytosol or intracellular fluid (ICF) or cytoplasmic matrix is the liquid found inside cells. It is separated intocompartments by membranes. For example, the mitochondrial matrix separates the mitochondrion intocompartments.In the eukaryotic cell, the cytosol is within the cell membrane and is part of the cytoplasm, which also comprises themitochondria, plastids, and other organelles (but not their internal fluids and structures); the cell nucleus is separate.In prokaryotes, most of the chemical reactions of metabolism take place in the cytosol, while a few take place inmembranes or in the periplasmic space. In eukaryotes, while many metabolic pathways still occur in the cytosol,others are contained within organelles.The cytosol is a complex mixture of substances dissolved in water. Although water forms the large majority of thecytosol, its structure and properties within cells is not well understood. The concentrations of ions such as sodiumand potassium are different in the cytosol than in the extracellular fluid; these differences in ion levels are importantin processes such as osmoregulation and cell signaling. The cytosol also contains large amounts of macromolecules,which can alter how molecules behave, through macromolecular crowding.Although once thought to be a simple solution of molecules, multiple levels of organization exist in the cytosol.These include concentration gradients of small molecules such as calcium, large complexes of enzymes that acttogether to carry out metabolic pathways, and protein complexes such as proteasomes and carboxysomes thatenclose and separate parts of the cytosol.

DefinitionThe term cytosol was first introduced in 1965 by H.A. Lardy, and initially referred to the liquid that was produced bybreaking cells apart and pelleting all the insoluble components by ultracentrifugation. Such a soluble cell extract isnot identical to the soluble part of the cell cytoplasm and is usually called a cytoplasmic fraction. The term cytosol isnow used to refer to the liquid phase of the cytoplasm in an intact cell, this excludes any part of the cytoplasm that iscontained within organelles. Due to the possibility of confusion between the use of the word "cytosol" to refer toboth extracts of cells and the soluble part of the cytoplasm in intact cells, the phrase "aqueous cytoplasm" has beenused to describe the liquid contents of the cytoplasm of living cells.

Properties and compositionThe proportion of cell volume that is cytosol varies: for example while this compartment forms the bulk of cellstructure in bacteria, in plant cells the main compartment is the large central vacuole. The cytosol consists mostly ofwater, dissolved ions, small molecules, and large water-soluble molecules (such as proteins). The majority of thesenon-protein molecules have a molecular mass of less than 300 Da. This mixture of small molecules is extraordinarilycomplex, as the variety of molecules that are involved in metabolism (the metabolites) is immense. For example upto 200,000 different small molecules might be made in plants, although not all these will be present in the samespecies, or in a single cell. Indeed, estimates of the number of metabolites in single cells such as E. coli and baker'syeast predict that under 1,000 are made.

WaterMost of the cytosol is water, which makes up about 70% of the total volume of a typical cell. The pH of theintracellular fluid is 7.4. while human cytosolic pH ranges between 7.0 - 7.4, and is usually higher if a cell isgrowing. The viscosity of cytoplasm is roughly the same as pure water, although diffusion of small moleculesthrough this liquid is about fourfold slower than in pure water, due mostly to collisions with the large numbers ofmacromolecules in the cytosol. Studies in the brine shrimp have examined how water affects cell functions; thesesaw that a 20% reduction in the amount of water in a cell inhibits metabolism, with metabolism decreasingprogressively as the cell dries out and all metabolic activity halting when the water level reaches 70% below normal.

Cytosol 22

Although water is vital for life, the structure of this water in the cytosol is not well understood, mostly becausemethods such as nuclear magnetic resonance only give information on the average structure of water, and cannotmeasure local variations at the microscopic scale. Even the structure of pure water is poorly understood, due to theability of water to form structures such as water clusters through hydrogen bonds.The classic view of water in cells is that about 5% of this water is strongly bound in by solutes or macromolecules aswater of solvation, while the majority has the same structure as pure water. This water of solvation is not active inosmosis and may have different solvent properties, so that some dissolved molecules are excluded, while othersbecome concentrated. However, others argue that the effects of the high concentrations of macromolecules in cellsextend throughout the cytosol and that water in cells behaves very differently from the water in dilute solutions.These ideas include the proposal that cells contain zones of low and high-density water, which could havewidespread effects on the structures and functions of the other parts of the cell. However, the use of advancednuclear magnetic resonance methods to directly measure the mobility of water in living cells contradicts this idea, asit suggests that 85% of cell water acts like that pure water, while the remainder is less mobile and probably bound tomacromolecules.

IonsThe concentrations of the other ions in cytosol are quite different from those in extracellular fluid and the cytosolalso contains much higher amounts of charged macromolecules such as proteins and nucleic acids than the outside ofthe cell.

Typical ion concentrations in mammalian cytosol and blood.

Ion  Concentration in cytosol (millimolar)   Concentration in blood (millimolar) 

Potassium 139 4

Sodium 12 145

Chloride 4 116

Bicarbonate 12 29

Amino acids in proteins 138 9

Magnesium 0.8 1.5

Calcium <0.0002 1.8

In contrast to extracellular fluid, cytosol has a high concentration of potassium ions and a low concentration ofsodium ions. This difference in ion concentrations is critical for osmoregulation, since if the ion levels were the sameinside a cell as outside, water would enter constantly by osmosis - since the levels of macromolecules inside cells arehigher than their levels outside. Instead, sodium ions are expelled and potassium ions taken up by theNa⁺/K⁺-ATPase, potassium ions then flow down their concentration gradient through potassium-selection ionchannels, this loss of positive charge creates a negative membrane potential. To balance this potential difference,negative chloride ions also exit the cell, through selective chloride channels. The loss of sodium and chloride ionscompensates for the osmotic effect of the higher concentration of organic molecules inside the cell.Cells can deal with even larger osmotic changes by accumulating osmoprotectants such as betaines or trehalose intheir cytosol. Some of these molecules can allow cells to survive being completely dried out and allow an organismto enter a state of suspended animation called cryptobiosis. In this state the cytosol and osmoprotectants become aglass-like solid that helps stabilize proteins and cell membranes from the damaging effects of desiccation.The low concentration of calcium in the cytosol allows calcium ions to function as a second messenger in calcium signaling. Here, a signal such as a hormone or an action potential opens calcium channels so that calcium floods into the cytosol. This sudden increase in cytosolic calcium activates other signalling molecules, such as calmodulin and

Cytosol 23

protein kinase C. Other ions such as chloride and potassium may also have signaling functions in the cytosol, butthese are not well understood.

MacromoleculesProtein molecules that do not bind to cell membranes or the cytoskeleton are dissolved in the cytosol. The amount ofprotein in cells is extremely high, and approaches 200 mg/ml, occupying about 20-30% of the volume of the cytosol.However, measuring precisely how much protein is dissolved in cytosol in intact cells is difficult, since someproteins appear to be weakly associated with membranes or organelles in whole cells and are released into solutionupon cell lysis. Indeed, in experiments where the plasma membrane of cells were carefully disrupted using saponin,without damaging the other cell membranes, only about one quarter of cell protein was released. These cells werealso able to synthesize proteins if given ATP and amino acids, implying that many of the enzymes in cytosol arebound to the cytoskeleton. However, the idea that the majority of the proteins in cells are tightly bound in a networkcalled the microtrabecular lattice is now seen as unlikely.In prokaryotes the cytosol contains the cell's genome, within a structure known as a nucleoid. This is an irregularmass of DNA and associated proteins that control the transcription and replication of the bacterial chromosome andplasmids. In eukaryotes the genome is held within the cell nucleus, which is separated from the cytosol by nuclearpores that block the free diffusion of any molecule larger than about 10 nanometres in diameter.This high concentration of macromolecules in cytosol causes an effect called macromolecular crowding, which iswhen the effective concentration of other macromolecules is increased, since they have less volume to move in. Thiscrowding effect can produce large changes in both the rates and the position of chemical equilibrium of reactions inthe cytosol. It is particularly important in its ability to alter dissociation constants by favoring the association ofmacromolecules, such as when multiple proteins come together to form protein complexes, or when DNA-bindingproteins bind to their targets in the genome.

OrganizationAlthough the components of the cytosol are not separated into regions by cell membranes, these components do notalways mix randomly and several levels of organization can localize specific molecules to defined sites within thecytosol.

Concentration gradientsAlthough small molecules diffuse rapidly in the cytosol, concentration gradients can still be produced within thiscompartment. A well-studied example of these are the "calcium sparks" that are produced for a short period in theregion around an open calcium channel. These are about 2 micrometres in diameter and last for only a fewmilliseconds, although several sparks can merge to form larger gradients, called "calcium waves". Concentrationgradients of other small molecules, such as oxygen and adenosine triphosphate may be produced in cells aroundclusters of mitochondria, although these are less well understood.

Protein complexesProteins can associate to form protein complexes, these often contain a set of proteins with similar functions, such asenzymes that carry out several steps in the same metabolic pathway. This organization can allow substratechanneling, which is when the product of one enzyme is passed directly to the next enzyme in a pathway withoutbeing released into solution. Channeling can make a pathway more rapid and efficient than it would be if theenzymes were randomly distributed in the cytosol, and can also prevent the release of unstable reactionintermediates. Although a wide variety of metabolic pathways involve enzymes that are tightly bound to each other,others may involve more loosely associated complexes that are very difficult to study outside the cell. Consequently,the importance of these complexes for metabolism in general remains unclear.

Cytosol 24

Carboxysomes are protein-enclosed bacterial microcompartments within the cytosol. Onthe left is an electron microscope image of carboxysomes, and on the right a model of

their structure.

Protein compartments

Some protein complexes contain alarge central cavity that is isolatedfrom the remainder of the cytosol. Oneexample of such an enclosedcompartment is the proteasome. Here,a set of subunits form a hollow barrelcontaining proteases that degradecytosolic proteins. Since these wouldbe damaging if they mixed freely withthe remainder of the cytosol, the barrelis capped by a set of regulatory proteins that recognize proteins with a signal directing them for degradation (aubiquitin tag) and feed them into the proteolytic cavity.

Another large class of protein compartments are bacterial microcompartments, which are made of a protein shell thatencapsulates various enzymes. These compartments are typically about 100-200 nanometres across and made ofinterlocking proteins. A well-understood example is the carboxysome, which contains enzymes involved in carbonfixation such as RuBisCO.

Cytoskeletal sievingAlthough the cytoskeleton is not part of the cytosol, the presence of this network of filaments restricts the diffusionof large particles in the cell. For example, in several studies tracer particles larger than about 25 nanometres (aboutthe size of a ribosome) were excluded from parts of the cytosol around the edges of the cell and next to the nucleus.These "excluding compartments" may contain a much denser meshwork of actin fibres than the remainder of thecytosol. These microdomains could influence the distribution of large structures such as ribosomes and organelleswithin the cytosol by excluding them from some areas and concentrating them in others.

FunctionThe cytosol has no single function and is instead the site of multiple cell processes. Examples of these processesinclude signal transduction from the cell membrane to sites within the cell, such as the cell nucleus, or organelles.This compartment is also the site of many of the processes of cytokinesis, after the breakdown of the nuclearmembrane in mitosis. Another major function of cytosol is to transport metabolites from their site of production towhere they are used. This is relatively simple for water-soluble molecules, such as amino acids, which can diffuserapidly through the cytosol. However, hydrophobic molecules, such as fatty acids or sterols, can be transportedthrough the cytosol by specific binding proteins, which shuttle these molecules between cell membranes. Moleculestaken into the cell by endocytosis or on their way to be secreted can also be transported through the cytosol insidevesicles, which are small spheres of lipids that are moved along the cytoskeleton by motor proteins.The cytosol is the site of most metabolism in prokaryotes, and a large proportion of the metabolism of eukaryotes.For instance, in mammals about half of the proteins in the cell are localized to the cytosol. The most complete dataare available in yeast, where metabolic reconstructions indicate that the majority of both metabolic processes andmetabolites occur in the cytosol. Major metabolic pathways that occur in the cytosol in animals are proteinbiosynthesis, the pentose phosphate pathway, glycolysis and gluconeogenesis. The localization of pathways can bedifferent in other organisms, for instance fatty acid synthesis occurs in chloroplasts in plants and in apicoplasts inapicomplexa.

Cytosol 25

References

Further reading• Wheatley, Denys N.; Pollack, Gerald H.; Cameron, Ivan L. (2006). Water and the Cell. Berlin: Springer.

ISBN 1-4020-4926-9. OCLC  71298997 (http:/ / www. worldcat. org/ oclc/ 71298997).

Cytoplasm 26

Cytoplasm

Cell biologyThe animal cell

Components of a typical animal cell:

1.1. Nucleolus2.2. Nucleus3. Ribosome (little dots)4.4. Vesicle5.5. Rough endoplasmic reticulum6. Golgi apparatus (or "Golgi body")7.7. Cytoskeleton8.8. Smooth endoplasmic reticulum9.9. Mitochondrion10.10. Vacuole11. Cytosol (fluid that contains organelles)12.12. Lysosome13.13. Centrosome14.14. Cell membrane

The cytoplasm comprises cytosol – the gel-like substance enclosed within the cell membrane – and the organelles –the cell's internal sub-structures. All of the contents of the cells of prokaryote organisms (such as bacteria, whichlack a cell nucleus) are contained within the cytoplasm. Within the cells of eukaryote organisms the contents of thecell nucleus are separated from the cytoplasm, and are then called the nucleoplasm. The cytoplasm is about 80%water and usually colorless.It is within the cytoplasm that most cellular activities occur, such as many metabolic pathways including glycolysis,and processes such as cell division. The inner, granular mass is called the endoplasm and the outer, clear and glassylayer is called the cell cortex or the ectoplasm.Movement of calcium ions in and out of the cytoplasm is thought to be a signaling activity for metabolicprocesses.[1]

In plants, movements of the cytoplasm around vacuoles are known as cytoplasmic streaming.

Cytoplasm 27

ConstituentsThe cytoplasm has three major elements; the cytosol, organelles and inclusions.

CytosolThe cytosol is the portion of the cytoplasm not contained within membrane-bound organelles. Cytosol makes upabout 70% of the cell volume and is composed of water, salts and organic molecules.[2] The cytosol is a complexmixture of cytoskeleton filaments, dissolved molecules, and water that fills much of the volume of a cell. The cytosolalso contains the protein filaments that make up the cytoskeleton, as well as soluble proteins and small structuressuch as ribosomes, proteasomes, and the mysterious vault complexes. The inner, granular and more fluid portion ofthe cytoplasm is referred to as endoplasm.

Proteins in different cellular compartments and structures taggedwith green fluorescent protein

Due to this network of fibres and high concentrationsof dissolved macromolecules, such as proteins, aneffect called macromolecular crowding occurs and thecytosol does not act as an ideal solution. This crowdingeffect alters how the components of the cytosol interactwith each other.

Organelles

Organelles (literally "little organs"), are usuallymembrane-bound, and are structures inside the cell thathave specific functions. Some major organelles that aresuspended in the cytosol are the mitochondria, theendoplasmic reticulum, the Golgi apparatus, vacuoles,lysosomes, and in plant cells chloroplasts.

Cytoplasmic inclusions

The inclusions are small particles of insolublesubstances suspended in the cytosol. A huge range ofinclusions exist in different cell types, and range fromcrystals of calcium oxalate or silicon dioxide in plants,to granules of energy-storage materials such as starch,glycogen, or polyhydroxybutyrate. A particularlywidespread example are lipid droplets, which are spherical droplets composed of lipids and proteins that are used inboth prokaryotes and eukaryotes as a way of storing lipids such as fatty acids and sterols. Lipid droplets make upmuch of the volume of adipocytes, which are specialized lipid-storage cells, but they are also found in a range ofother cell types.

Controversy and researchThe cytoplasm, mitochondria and most organelles are contributions to the cell from the maternal gamete. There is considerably less research and understanding on cytoplasmic inheritance/maternal inheritance and mitochondrial DNA compared to the cell nucleus and genomic DNA. Historically, there has been neglect of researching whatever has been labeled female or feminine. The cytoplasm is one organelle that has been labeled feminine. The cytoplasm/nucleus being labeled as feminine/masculine follows the example of egg/sperm being gendered; both cytoplasm and egg are considered nonresistant to the efforts and pursuits of the active nucleus and sperm. The "passivity of the egg becomes the passivity of the cytoplasm." Contrary to the older information that disregards any

Cytoplasm 28

notion of the cytoplasm being active, new research has shown it to be in control of movement and flow of nutrientsin and out of the cell by "viscoplastic behavior and... a measure of the reciprocal rate of bond breakadge within thecytoplasmic network."

References[1] C. Michael Hogan. 2010. Calcium. eds. A.Jorgensen, C. Cleveland. Encyclopedia of Earth (http:/ / www. eoearth. org/ article/

Calcium?topic=49557). National Council for Science and the Environment.[2] Cytoplasm Composition (http:/ / web. archive. org/ web/ 20070331230518/ http:/ / sun. menloschool. org/ ~birchler/ cells/ animals/

cytoplasm/ ). menloschool.org

External links• Luby-Phelps K (2000). "Cytoarchitecture and physical properties of cytoplasm: volume, viscosity, diffusion,

intracellular surface area" (http:/ / www. rpgroup. caltech. edu/ courses/ aph161/ Handouts/ Luby-Phelps2000.pdf) (PDF). Int Rev Cytol. International Review of Cytology 192: 189–221. doi: 10.1016/S0074-7696(08)60527-6(http:/ / dx. doi. org/ 10. 1016/ S0074-7696(08)60527-6). ISBN 9780123645968. PMID  10553280 (http:/ / www.ncbi. nlm. nih. gov/ pubmed/ 10553280).

Organelle

OrganelleLatin organella

Code TH H1.00.01.0.00009 [1]

Cell biologyThe animal cell

Organelle 29

Components of a typical animal cell:

1.1. Nucleolus2.2. Nucleus3. Ribosome (little dots)4.4. Vesicle5.5. Rough endoplasmic reticulum6. Golgi apparatus (or "Golgi body")7.7. Cytoskeleton8.8. Smooth endoplasmic reticulum9.9. Mitochondrion10.10. Vacuole11. Cytosol (fluid that contains organelles)12.12. Lysosome13.13. Centrosome14.14. Cell membrane

In cell biology, an organelle /ɔrɡəˈnɛl/ is a specialized subunit within a cell that has a specific function, and it isusually separately enclosed within its own lipid bilayer.The name organelle comes from the idea that these structures are to cells what an organ is to the body (hence thename organelle, the suffix -elle being a diminutive). Organelles are identified by microscopy, and can also bepurified by cell fractionation. There are many types of organelles, particularly in eukaryotic cells. While prokaryotesdo not possess organelles per se, some do contain protein-based microcompartments, which are thought to act asprimitive organelles.

History and terminologyIn biology organs are defined as confined functional units within an organism. The analogy of bodily organs tomicroscopic cellular substructures is obvious, as from even early works, authors of respective textbooks rarelyelaborate on the distinction between the two.Credited as the first[2][3] to use a diminutive of organ (i.e., little organ) for cellular structures was German zoologistKarl August Möbius (1884), who used the term organula (plural of organulum, the diminutive of Latin organum).From the context, it is clear that he referred to reproduction related structures of protists. In a footnote, which waspublished as a correction in the next issue of the journal, he justified his suggestion to call organs of unicellularorganisms "organella" since they are only differently formed parts of one cell, in contrast to multicellular organs ofmulticellular organisms. Thus, the original definition was limited to structures of unicellular organisms.It would take several years before organulum, or the later term organelle, became accepted and expanded in meaningto include subcellular structures in multicellular organisms. Books around 1900 from Valentin Häcker, EdmundWilson and Oscar Hertwig still referred to cellular organs. Later, both terms came to be used side by side: BengtLidforss wrote 1915 (in German) about "Organs or Organells".

Organelle 30

Around 1920, the term organelle was used to describe propulsion structures ("motor organelle complex", i.e., flagellaand their anchoring) and other protist structures, such as ciliates.[4] Alfred Kühn wrote about centrioles as divisionorganelles, although he stated that, for Vahlkampfias, the alternative 'organelle' or 'product of structural build-up' hadnot yet been decided, without explaining the difference between the alternatives.In his 1953 textbook, Max Hartmann used the term for extracellular (pellicula, shells, cell walls) and intracellularskeletons of protists.Later, the now widely used[5][6][7][8] definition of organelle emerged, after which only cellular structures withsurrounding membrane had been considered organelles. However, the more original definition of subcellularfunctional unit in general still coexists.[9]

In 1978, Albert Frey-Wyssling suggested that the term organelle should refer only to structures that convert energy,such as centrosomes, ribosomes, and nucleoli. This new definition, however, did not win wide recognition.

Types of organellesWhile most cell biologists consider the term organelle to be synonymous with "cell compartment", other cellbiologists choose to limit the term organelle to include only those that are DNA-containing, having originated fromformerly autonomous microscopic organisms acquired via endosymbiosis.Under this definition, there would only be two broad classes of organelles (i.e. those that contain their own DNA,and have originated from endosymbiotic bacteria):• mitochondria (in almost all eukaryotes)• plastids[10] (e.g. in plants, algae, and some protists).Other organelles are also suggested to have endosymbiotic origins, but do not contain their own DNA (notably theflagellum – see evolution of flagella).Under the more restricted definition of membrane-bound structures, some parts of the cell do not qualify asorganelles. Nevertheless, the use of organelle to refer to non-membrane bound structures such as ribosomes iscommon.[11] This has led some texts to delineate between membrane-bound and non-membrane boundorganelles.[12] These structures are large assemblies of macromolecules that carry out particular and specializedfunctions, but they lack membrane boundaries. Such cell structures include:• large RNA and protein complexes: ribosome, spliceosome, vault• large protein complexes: proteasome, DNA polymerase III holoenzyme, RNA polymerase II holoenzyme,

symmetric viral capsids, complex of GroEL and GroES; membrane protein complexes: photosystem I, ATPsynthase

• large DNA and protein complexes: nucleosome• centriole and microtubule-organizing center (MTOC)•• cytoskeleton•• flagellum•• cellular structure which is not membrane bound and does not have a well-defined structure: nucleolus

Organelle 31

Eukaryotic organellesEukaryotic cells are structurally complex, and by definition are organized, in part, by interior compartments that arethemselves enclosed by lipid membranes that resemble the outermost cell membrane. The larger organelles, such asthe nucleus and vacuoles, are easily visible with the light microscope. They were among the first biologicaldiscoveries made after the invention of the microscope.Not all eukaryotic cells have each of the organelles listed below. Exceptional organisms have cells that do notinclude some organelles that might otherwise be considered universal to eukaryotes (such as mitochondria). Thereare also occasional exceptions to the number of membranes surrounding organelles, listed in the tables below (e.g.,some that are listed as double-membrane are sometimes found with single or triple membranes). In addition, thenumber of individual organelles of each type found in a given cell varies depending upon the function of that cell.

Major eukaryotic organelles

Organelle Main function Structure Organisms Notes

chloroplast(plastid)

photosynthesis, traps energy from sunlight double-membranecompartment

plants, protists(rare kleptoplasticorganisms)

has some genes; theorized to be engulfedby the ancestral eukaryotic cell(endosymbiosis)

endoplasmicreticulum

translation and folding of new proteins(rough endoplasmic reticulum), expressionof lipids (smooth endoplasmic reticulum)

single-membranecompartment

all eukaryotes rough endoplasmic reticulum is coveredwith ribosomes, has folds that are flatsacs; smooth endoplasmic reticulum hasfolds that are tubular

Golgiapparatus

sorting, packaging, processing andmodification of proteins

single-membranecompartment

all eukaryotes cis-face (convex) nearest to roughendoplasmic reticulum; trans-face(concave) farthest from roughendoplasmic reticulum

mitochondria energy production from the oxidation ofglucose substances and the release ofadenosine triphosphate

double-membranecompartment

most eukaryotes has some DNA; theorized to be engulfedby an ancestral eukaryotic cell(endosymbiosis)

vacuole storage,transportation, helps maintainhomeostasis

single-membranecompartment

eukaryotes

nucleus DNA maintenance, controls all activitiesof the cell, RNA transcription

double-membranecompartment

all eukaryotes contains bulk of genome

Mitochondria and chloroplasts, which have double-membranes and their own DNA, are believed to have originatedfrom incompletely consumed or invading prokaryotic organisms, which were adopted as a part of the invaded cell.This idea is supported in the Endosymbiotic theory.

Minor eukaryotic organelles and cell components

Organelle/Macromolecule Main function Structure Organisms

acrosome helps spermatozoa fuse with ovum single-membranecompartment

many animals

autophagosome vesicle that sequesters cytoplasmic materialand organelles for degradation

double-membranecompartment

all eukaryotes

centriole anchor for cytoskeleton, organizes celldivision by forming spindle fibers

Microtubule protein animals

cilium movement in or of external medium; "criticaldevelopmental signaling pathway".

Microtubule protein animals, protists, few plants

Organelle 32

eyespot apparatus detects light, allowing phototaxis to takeplace

green algae and other unicellularphotosynthetic organisms such aseuglenids

glycosome carries out glycolysis single-membranecompartment

Some protozoa, such as Trypanosomes.

glyoxysome conversion of fat into sugars single-membranecompartment

plants

hydrogenosome energy & hydrogen production double-membranecompartment

a few unicellular eukaryotes

lysosome breakdown of large molecules (e.g., proteins+ polysaccharides)

single-membranecompartment

most eukaryotes

melanosome pigment storage single-membranecompartment

animals

mitosome probably plays a role in Fe-S cluster assembly double-membranecompartment

a few unicellular eukaryotes that lackmitochondria

myofibril myocyte contraction bundled filaments animals

nucleolus pre-ribosome production protein-DNA-RNA most eukaryotes

parenthesome not characterized not characterized fungi

peroxisome breakdown of metabolic hydrogen peroxide single-membranecompartment

all eukaryotes

proteasome degradation of unneeded or damaged proteinsby proteolysis

very large proteincomplex

All eukaryotes, all archaea, some bacteria

ribosome (80S) translation of RNA into proteins RNA-protein all eukaryotes

vesicle material transport single-membranecompartment

all eukaryotes

Other related structures:•• cytosol•• endomembrane system•• nucleosome•• microtubule•• cell membrane

(A) Electron micrograph of Halothiobacillus neapolitanus cells, arrows highlightcarboxysomes. (B) Image of intact carboxysomes isolated from H. neapolitanus. Scale

bars are 100 nm.

Prokaryotic organelles

Prokaryotes are not as structurallycomplex as eukaryotes, and were oncethought not to have any internalstructures enclosed by lipidmembranes. In the past, they wereoften viewed as having little internalorganization; but, slowly, details areemerging about prokaryotic internalstructures. An early false turn was theidea developed in the 1970s thatbacteria might contain membrane folds termed mesosomes, but these were later shown to be artifacts produced bythe chemicals used to prepare the cells for electron microscopy.

Organelle 33

However, more recent research has revealed that at least some prokaryotes have microcompartments such ascarboxysomes. These subcellular compartments are 100–200 nm in diameter and are enclosed by a shell of proteins.Even more striking is the description of membrane-bound magnetosomes in bacteria, as well as the nucleus-likestructures of the Planctomycetes that are surrounded by lipid membranes.

Prokaryotic organelles and cell components

Organelle/Macromolecule Main function Structure Organisms

carboxysome carbon fixation protein-shell compartment some bacteria

chlorosome photosynthesis light harvesting complex green sulfur bacteria

flagellum movement in external medium protein filament some prokaryotes and eukaryotes

magnetosome magnetic orientation inorganic crystal, lipid membrane magnetotactic bacteria

nucleoid DNA maintenance, transcription toRNA

DNA-protein prokaryotes

plasmid DNA exchange circular DNA some bacteria

ribosome (70S) translation of RNA into proteins RNA-protein bacteria and archaea

thylakoid photosynthesis photosystem proteins and pigments mostly cyanobacteria

mesosomes functions of golgi bodies,centriolesetc..

small irregular shaped oraganelle containingribosomes

present in most of theprokaryotic cells

Proteins and organellesThe function of a protein is closely correlated with the organelle in which it resides. Some methods were proposedfor predicting the organelle in which an uncharacterized protein is located according to its amino acid compositionand some methods were based on pseudo amino acid composition.

References[1] http:/ / www. unifr. ch/ ifaa/ Public/ EntryPage/ ViewTH/ THh100. html[2] Amer. Naturalist. 23, 1889, p. 183: "It may possibly be of advantage to use the word organula here instead of organ, following a suggestion

by Möbius. Functionally differentiated multicellular aggregates in multicellular forms or metazoa are in this sense organs, while, forfunctionally differentiated portions of unicellular organisms or for such differentiated portions of the unicellular germ-elements of metazoa,the diminutive organula is appropriate." Cited after: Oxford English Dictionary online, entry for "organelle".

[3] 'Journal de l'anatomie et de la physiologie normales et pathologiques de l'homme et des animaux' at Google Books (http:/ / books. google.com/ books?id=yAQwAAAAIAAJ& q=Organulum+ OR+ Organula+ OR+ Organella+ date:1800-1900& dq=Organulum+ OR+ Organula+OR+ Organella+ date:1800-1900& as_brr=0& pgis=1)

[4] Cl. Hamburger, Handwörterbuch der Naturw. Bd. V,. p. 435. Infusorien. cited after[5] Nultsch, Allgemeine Botanik, 11. Aufl. 2001, Thieme Verlag[6] Wehner/Gehring, Zoologies, 23. Aufl. 1995, Thieme Verlag[7] Alberts, Bruce et al. (2002). The Molecular Biology of the Cell, 4th ed., Garland Science, 2002, ISBN 0-8153-3218-1. online via

"NCBI-Bookshelf" (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=Books& itool=toolbar)[8][8] Brock, Mikrobiologie, 2. korrigierter Nachdruck (2003), der 1. Aufl. von 2001[9] Strasburgers Lehrbuch der Botanik für Hochschulen, 35. Aufl. (2002), p. 42[10] C.Michael Hogan. 2010. Deoxyribonucleic acid. Encyclopedia of Earth. National Council for Science and the Environment. (http:/ / www.

eoearth. org/ articles/ view/ 158858/ ?topic=49496) S. Draggan and C. Cleveland (eds.). Washington DC[11] Campbell and Reece, Biology 6th edition, Benjamin Cummings, 2002[12] Cormack, David H. (1984) Introduction to Histology, Lippincott, ISBN 0397521146

Organelle 34

External links• Tree of Life Eukaryotes (http:/ / tolweb. org/ Eukaryotes/ 3)

Library resources

About Organelle

• Resources in your library (http:/ / tools. wmflabs. org/ ftl/ cgi-bin/ ftl?st=wp& su=Organelle)

Cell nucleus

Cell biologyThe animal cell

Components of a typical animal cell:

1.1. Nucleolus2.2. Nucleus3. Ribosome (little dots)4.4. Vesicle5.5. Rough endoplasmic reticulum6. Golgi apparatus (or "Golgi body")7.7. Cytoskeleton8.8. Smooth endoplasmic reticulum9.9. Mitochondrion10.10. Vacuole11. Cytosol (fluid that contains organelles)12.12. Lysosome13.13. Centrosome14.14. Cell membrane

In cell biology, the nucleus (pl. nuclei; from Latin nucleus or nuculeus, meaning kernel) is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these chromosomes are the cell's nuclear genome. The function of the nucleus is to maintain the integrity of these genes and to control the activities of the cell by regulating gene expression — the nucleus is, therefore, the control center of the cell. The main structures making up the nucleus are the nuclear envelope, a double membrane that encloses the entire organelle and isolates its contents from the cellular cytoplasm, and the nucleoskeleton (which includes nuclear lamina), a network within the nucleus that adds mechanical support, much like the cytoskeleton, which supports the cell as a whole. Movement of large molecules such as proteins and RNA through the pores is required for both gene expression and the maintenance of chromosomes. Because the nuclear membrane is

Cell nucleus 35

impermeable to large molecules, nuclear pores are required that regulate nuclear transport of molecules across theenvelope. The pores cross both nuclear membranes, providing a channel through which larger molecules must beactively transported by carrier proteins while allowing free movement of small molecules and ions. The interior ofthe nucleus does not contain any membrane-bound sub compartments, its contents are not uniform, and a number ofsub-nuclear bodies exist, made up of unique proteins, RNA molecules, and particular parts of the chromosomes. Thebest-known of these is the nucleolus, which is mainly involved in the assembly of ribosomes. After being producedin the nucleolus, ribosomes are exported to the cytoplasm where they translate mRNA.

History

Oldest known depiction of cells and their nuclei by Antonie vanLeeuwenhoek, 1719.

Drawing of a Chironomus salivary gland cellpublished by Walther Flemming in 1882. The

nucleus contains Polytene chromosomes.

The nucleus was the first organelle to bediscovered. What is most likely the oldestpreserved drawing dates back to the earlymicroscopist Antonie van Leeuwenhoek (1632 –1723). He observed a "Lumen", the nucleus, in thered blood cells of salmon.[1] Unlike mammalianred blood cells, those of other vertebrates stillpossess nuclei. The nucleus was also described byFranz Bauer in 1804 and in more detail in 1831 byScottish botanist Robert Brown in a talk at theLinnean Society of London. Brown was studyingorchids under microscope when he observed anopaque area, which he called the areola or nucleus,in the cells of the flower's outer layer. He did notsuggest a potential function. In 1838, MatthiasSchleiden proposed that the nucleus plays a role ingenerating cells, thus he introduced the name"Cytoblast" (cell builder). He believed that he hadobserved new cells assembling around"cytoblasts". Franz Meyen was a strong opponentof this view, having already described cellsmultiplying by division and believing that manycells would have no nuclei. The idea that cells canbe generated de novo, by the "cytoblast" orotherwise, contradicted work by Robert Remak

(1852) and Rudolf Virchow (1855) who decisively propagated the new paradigm that cells are generated solely bycells ("Omnis cellula e cellula"). The function of the nucleus remained unclear.[2]

Between 1877 and 1878, Oscar Hertwig published several studies on the fertilization of sea urchin eggs, showingthat the nucleus of the sperm enters the oocyte and fuses with its nucleus. This was the first time it was suggestedthat an individual develops from a (single) nucleated cell. This was in contradiction to Ernst Haeckel's theory that thecomplete phylogeny of a species would be repeated during embryonic development, including generation of the firstnucleated cell from a "Monerula", a structureless mass of primordial mucus ("Urschleim"). Therefore, the necessityof the sperm nucleus for fertilization was discussed for quite some time. However, Hertwig confirmed hisobservation in other animal groups, e.g., amphibians and molluscs. Eduard Strasburger produced the same results forplants (1884). This paved the way to assign the nucleus an important role in heredity. In 1873, August Weismann

Cell nucleus 36

postulated the equivalence of the maternal and paternal germ cells for heredity. The function of the nucleus as carrierof genetic information became clear only later, after mitosis was discovered and the Mendelian rules wererediscovered at the beginning of the 20th century; the chromosome theory of heredity was therefore developed.

StructuresThe nucleus is the largest cellular organelle in animals. In mammalian cells, the average diameter of the nucleus isapproximately 6 micrometers (μm), which occupies about 10% of the total cell volume. The viscous liquid within itis called nucleoplasm, and is similar in composition to the cytosol found outside the nucleus. It appears as a dense,roughly spherical organelle.

Nuclear envelope and pores

The eukaryotic cell nucleus. Visible in this diagram are theribosome-studded double membranes of the nuclear envelope, theDNA (complexed as chromatin), and the nucleolus. Within the cell

nucleus is a viscous liquid called nucleoplasm, similar to thecytoplasm found outside the nucleus.

A cross section of a nuclear pore on the surface of the nuclearenvelope (1). Other diagram labels show (2) the outer ring, (3)

spokes, (4) basket, and (5) filaments.

The nuclear envelope, otherwise known as nuclear membrane, consists of two cellular membranes, an inner and anouter membrane, arranged parallel to one another and separated by 10 to 50 nanometers (nm). The nuclear envelopecompletely encloses the nucleus and separates the cell's genetic material from the surrounding cytoplasm, serving asa barrier to prevent macromolecules from diffusing freely between the nucleoplasm and the cytoplasm. The outernuclear membrane is continuous with the membrane of the rough endoplasmic reticulum (RER), and is similarlystudded with ribosomes. The space between the membranes is called the perinuclear space and is continuous with theRER lumen.Nuclear pores, which provide aqueous channels through the envelope, are composed of multiple proteins, collectively referred to as nucleoporins. The pores are about 125 million daltons in molecular weight and consist of around 50 (in yeast) to several hundred proteins (in vertebrates). The pores are 100 nm in total diameter; however, the gap through which molecules freely diffuse is only about 9 nm wide, due to the presence of regulatory systems within the center of the pore. This size selectively allows the passage of small water-soluble molecules while preventing larger molecules, such as nucleic acids and larger proteins, from inappropriately entering or exiting the nucleus. These large molecules must be actively transported into the nucleus instead. The nucleus of a typical mammalian cell will have about 3000 to 4000 pores throughout its envelope, each of which contains an eightfold-symmetric ring-shaped structure at a position where the inner and outer membranes fuse. Attached to the

Cell nucleus 37

ring is a structure called the nuclear basket that extends into the nucleoplasm, and a series of filamentous extensionsthat reach into the cytoplasm. Both structures serve to mediate binding to nuclear transport proteins.Most proteins, ribosomal subunits, and some DNAs are transported through the pore complexes in a processmediated by a family of transport factors known as karyopherins. Those karyopherins that mediate movement intothe nucleus are also called importins, whereas those that mediate movement out of the nucleus are called exportins.Most karyopherins interact directly with their cargo, although some use adaptor proteins. Steroid hormones such ascortisol and aldosterone, as well as other small lipid-soluble molecules involved in intercellular signaling, can diffusethrough the cell membrane and into the cytoplasm, where they bind nuclear receptor proteins that are trafficked intothe nucleus. There they serve as transcription factors when bound to their ligand; in the absence of ligand, many suchreceptors function as histone deacetylases that repress gene expression.

Nuclear laminaIn animal cells, two networks of intermediate filaments provide the nucleus with mechanical support: The nuclearlamina forms an organized meshwork on the internal face of the envelope, while less organized support is providedon the cytosolic face of the envelope. Both systems provide structural support for the nuclear envelope andanchoring sites for chromosomes and nuclear pores.The nuclear lamina is composed mostly of lamin proteins. Like all proteins, lamins are synthesized in the cytoplasmand later transported to the nucleus interior, where they are assembled before being incorporated into the existingnetwork of nuclear lamina. Lamins found on the cytosolic face of the membrane, such as emerin and nesprin, bind tothe cytoskeleton to provide structural support. Lamins are also found inside the nucleoplasm where they formanother regular structure, known as the nucleoplasmic veil, that is visible using fluorescence microscopy. The actualfunction of the veil is not clear, although it is excluded from the nucleolus and is present during interphase. Laminstructures that make up the veil, such as LEM3, bind chromatin and disrupting their structure inhibits transcription ofprotein-coding genes.Like the components of other intermediate filaments, the lamin monomer contains an alpha-helical domain used bytwo monomers to coil around each other, forming a dimer structure called a coiled coil. Two of these dimerstructures then join side by side, in an antiparallel arrangement, to form a tetramer called a protofilament. Eight ofthese protofilaments form a lateral arrangement that is twisted to form a ropelike filament. These filaments can beassembled or disassembled in a dynamic manner, meaning that changes in the length of the filament depend on thecompeting rates of filament addition and removal.Mutations in lamin genes leading to defects in filament assembly are known as laminopathies. The most notablelaminopathy is the family of diseases known as progeria, which causes the appearance of premature aging in itssufferers. The exact mechanism by which the associated biochemical changes give rise to the aged phenotype is notwell understood.

Cell nucleus 38

Chromosomes

A mouse fibroblast nucleus in which DNA is stainedblue. The distinct chromosome territories of

chromosome 2 (red) and chromosome 9 (green) arestained with fluorescent in situ hybridization.

The cell nucleus contains the majority of the cell's genetic materialin the form of multiple linear DNA molecules organized intostructures called chromosomes. Each human cell contains roughlytwo meters of DNA. During most of the cell cycle these areorganized in a DNA-protein complex known as chromatin, andduring cell division the chromatin can be seen to form thewell-defined chromosomes familiar from a karyotype. A smallfraction of the cell's genes are located instead in the mitochondria.

There are two types of chromatin. Euchromatin is the less compactDNA form, and contains genes that are frequently expressed bythe cell. The other type, heterochromatin, is the more compactform, and contains DNA that is infrequently transcribed. Thisstructure is further categorized into facultative heterochromatin,consisting of genes that are organized as heterochromatin only incertain cell types or at certain stages of development, andconstitutive heterochromatin that consists of chromosomestructural components such as telomeres and centromeres. Duringinterphase the chromatin organizes itself into discrete individual patches, called chromosome territories. Activegenes, which are generally found in the euchromatic region of the chromosome, tend to be located towards thechromosome's territory boundary.

Antibodies to certain types of chromatin organization, in particular, nucleosomes, have been associated with anumber of autoimmune diseases, such as systemic lupus erythematosus. These are known as anti-nuclear antibodies(ANA) and have also been observed in concert with multiple sclerosis as part of general immune systemdysfunction. As in the case of progeria, the role played by the antibodies in inducing the symptoms of autoimmunediseases is not obvious.

Nucleolus

An electron micrograph of a cell nucleus, showing thedarkly stained nucleolus.

The nucleolus is a discrete densely stained structure found in thenucleus. It is not surrounded by a membrane, and is sometimescalled a suborganelle. It forms around tandem repeats of rDNA,DNA coding for ribosomal RNA (rRNA). These regions are callednucleolar organizer regions (NOR). The main roles of thenucleolus are to synthesize rRNA and assemble ribosomes. Thestructural cohesion of the nucleolus depends on its activity, asribosomal assembly in the nucleolus results in the transientassociation of nucleolar components, facilitating further ribosomalassembly, and hence further association. This model is supportedby observations that inactivation of rDNA results in interminglingof nucleolar structures.

In the first step of ribosome assembly, a protein called RNApolymerase I transcribes rDNA, which forms a large pre-rRNAprecursor. This is cleaved into the subunits 5.8S, 18S, and 28S

Cell nucleus 39

3D rendering of nucleus with location ofnucleolus

rRNA. The transcription, post-transcriptional processing, and assemblyof rRNA occurs in the nucleolus, aided by small nucleolar RNA(snoRNA) molecules, some of which are derived from spliced intronsfrom messenger RNAs encoding genes related to ribosomal function.The assembled ribosomal subunits are the largest structures passedthrough the nuclear pores.

When observed under the electron microscope, the nucleolus can beseen to consist of three distinguishable regions: the innermost fibrillarcenters (FCs), surrounded by the dense fibrillar component (DFC),which in turn is bordered by the granular component (GC).Transcription of the rDNA occurs either in the FC or at the FC-DFCboundary, and, therefore, when rDNA transcription in the cell isincreased, more FCs are detected. Most of the cleavage andmodification of rRNAs occurs in the DFC, while the latter stepsinvolving protein assembly onto the ribosomal subunits occur in theGC.

Other subnuclear bodies

Structure name Structure diameter

Cajal bodies 0.2–2.0 µmPIKA 5 µmPML bodies 0.2–1.0 µmParaspeckles 0.2–1.0 µmSpeckles 20–25 nm

|+ Subnuclear structure sizes Besides the nucleolus, the nucleus contains a number of othernon-membrane-delineated bodies. These include Cajal bodies, Gemini of coiled bodies, polymorphic interphasekaryosomal association (PIKA), promyelocytic leukaemia (PML) bodies, paraspeckles, and splicing speckles.Although little is known about a number of these domains, they are significant in that they show that thenucleoplasm is not uniform mixture, but rather contains organized functional subdomains.Other subnuclear structures appear as part of abnormal disease processes. For example, the presence of smallintranuclear rods has been reported in some cases of nemaline myopathy. This condition typically results frommutations in actin, and the rods themselves consist of mutant actin as well as other cytoskeletal proteins.

Cajal bodies and gems

A nucleus typically contains between 1 and 10 compact structures called Cajal bodies or coiled bodies (CB), whosediameter measures between 0.2 µm and 2.0 µm depending on the cell type and species. When seen under an electronmicroscope, they resemble balls of tangled thread and are dense foci of distribution for the protein coilin. CBs areinvolved in a number of different roles relating to RNA processing, specifically small nucleolar RNA (snoRNA) andsmall nuclear RNA (snRNA) maturation, and histone mRNA modification.Similar to Cajal bodies are Gemini of coiled bodies, or gems, whose name is derived from the Gemini constellation in reference to their close "twin" relationship with CBs. Gems are similar in size and shape to CBs, and in fact are virtually indistinguishable under the microscope. Unlike CBs, gems do not contain small nuclear ribonucleoproteins (snRNPs), but do contain a protein called survivor of motor neurons (SMN) whose function relates to snRNP

Cell nucleus 40

biogenesis. Gems are believed to assist CBs in snRNP biogenesis, though it has also been suggested frommicroscopy evidence that CBs and gems are different manifestations of the same structure.

RAFA and PTF domains

RAFA domains, or polymorphic interphase karyosomal associations, were first described in microscopy studies in1991. Their function was and remains unclear, though they were not thought to be associated with active DNAreplication, transcription, or RNA processing.[3] They have been found to often associate with discrete domainsdefined by dense localization of the transcription factor PTF, which promotes transcription of snRNA.

PML bodies

Promyelocytic leukaemia bodies (PML bodies) are spherical bodies found scattered throughout the nucleoplasm,measuring around 0.1–1.0 µm. They are known by a number of other names, including nuclear domain 10 (ND10),Kremer bodies, and PML oncogenic domains. PML bodies are named after one of their major components, thePromyelocytic leukemia protein. They are often seen in the nucleus in association with Cajal bodies and cleavagebodies. PML bodies belong to the nuclear matrix, an ill-defined super-structure of the nucleus proposed to anchorand regulate many nuclear functions, including DNA replication, transcription, or epigenetic silencing. The PMLprotein is the key organizer of these domains that recruits an ever-growing number of proteins, whose only commonknown feature to date is their ability to be sumoylated. Yet, pml-/- mice (which have their PML gene deleted) cannotassemble nuclear bodies, develop normally and live well, demonstrating that PML bodies are dispensable for mostbasic biological functions.

Paraspeckles

Discovered by Fox et al. in 2002, paraspeckles are irregularly shaped compartments in the nucleus' interchromatinspace. First documented in HeLa cells, where there are generally 10–30 per nucleus, paraspeckles are now known toalso exist in all human primary cells, transformed cell lines, and tissue sections. Their name is derived from theirdistribution in the nucleus; the "para" is short for parallel and the "speckles" refers to the splicing speckles to whichthey are always in close proximity.Paraspeckles are dynamic structures that are altered in response to changes in cellular metabolic activity. They aretranscription dependent and in the absence of RNA Pol II transcription, the paraspeckle disappears and all of itsassociated protein components (PSP1, p54nrb, PSP2, CFI(m)68, and PSF) form a crescent shaped perinucleolar capin the nucleolus. This phenomenon is demonstrated during the cell cycle. In the cell cycle, paraspeckles are presentduring interphase and during all of mitosis except for telophase. During telophase, when the two daughter nuclei areformed, there is no RNA Pol II transcription so the protein components instead form a perinucleolar cap.

Splicing speckles

Speckles are subnuclear structures that are enriched in pre-messenger RNA splicing factors and are located in the interchromatin regions of the nucleoplasm of mammalian cells. At the fluorescence-microscope level they appear as irregular, punctate structures, which vary in size and shape, and when examined by electron microscopy they are seen as clusters of interchromatin granules. Speckles are dynamic structures, and both their protein and RNA-protein components can cycle continuously between speckles and other nuclear locations, including active transcription sites. Studies on the composition, structure and behaviour of speckles have provided a model for understanding the functional compartmentalization of the nucleus and the organization of the gene-expression machinery. splicing snRNPs and other splicing proteins necessary for pre-mRNA processing. Because of a cell's changing requirements, the composition and location of these bodies changes according to mRNA transcription and regulation via phosphorylation of specific proteins. The splicing speckles are also known as nuclear speckles (nuclear specks), splicing factor compartments (SF compartments), interchromatin granule clusters (IGCs), B snurposomes. B snurposomes are found in the amphibian oocyte nuclei and in Drosophila melanogaster embryos. B snurposomes

Cell nucleus 41

appear alone or attached to the Cajal bodies in the electron micrographs of the amphibian nuclei. IGCs function asstorage sites for the splicing factors.

Perichromatin fibrils

Perichromatin fibrils are visible only under electron microscope. They are located next to the transcriptionally activechromatin and is hypothesized to be the site of active pre-mRNA processing.

FunctionThe nucleus provides a site for genetic transcription that is segregated from the location of translation in thecytoplasm, allowing levels of gene regulation that are not available to prokaryotes. The main function of the cellnucleus is to control gene expression and mediate the replication of DNA during the cell cycle.

Cell compartmentalizationThe nuclear envelope allows the nucleus to control its contents, and separate them from the rest of the cytoplasmwhere necessary. This is important for controlling processes on either side of the nuclear membrane. In most caseswhere a cytoplasmic process needs to be restricted, a key participant is removed to the nucleus, where it interactswith transcription factors to downregulate the production of certain enzymes in the pathway. This regulatorymechanism occurs in the case of glycolysis, a cellular pathway for breaking down glucose to produce energy.Hexokinase is an enzyme responsible for the first the step of glycolysis, forming glucose-6-phosphate from glucose.At high concentrations of fructose-6-phosphate, a molecule made later from glucose-6-phosphate, a regulator proteinremoves hexokinase to the nucleus, where it forms a transcriptional repressor complex with nuclear proteins toreduce the expression of genes involved in glycolysis.[4]

In order to control which genes are being transcribed, the cell separates some transcription factor proteinsresponsible for regulating gene expression from physical access to the DNA until they are activated by othersignaling pathways. This prevents even low levels of inappropriate gene expression. For example, in the case ofNF-κB-controlled genes, which are involved in most inflammatory responses, transcription is induced in response toa signal pathway such as that initiated by the signaling molecule TNF-α, binds to a cell membrane receptor, resultingin the recruitment of signalling proteins, and eventually activating the transcription factor NF-κB. A nuclearlocalisation signal on the NF-κB protein allows it to be transported through the nuclear pore and into the nucleus,where it stimulates the transcription of the target genes.The compartmentalization allows the cell to prevent translation of unspliced mRNA. Eukaryotic mRNA containsintrons that must be removed before being translated to produce functional proteins. The splicing is done inside thenucleus before the mRNA can be accessed by ribosomes for translation. Without the nucleus, ribosomes wouldtranslate newly transcribed (unprocessed) mRNA, resulting in misformed and nonfunctional proteins.

Cell nucleus 42

Gene expression

A micrograph of ongoing gene transcription ofribosomal RNA illustrating the growing primary

transcripts. "Begin" indicates the 5' end of the DNA,where new RNA synthesis begins; "end" indicates the

3' end, where the primary transcripts are almostcomplete.

Gene expression first involves transcription, in which DNA is usedas a template to produce RNA. In the case of genes encodingproteins, that RNA produced from this process is messenger RNA(mRNA), which then needs to be translated by ribosomes to forma protein. As ribosomes are located outside the nucleus, mRNAproduced needs to be exported.

Since the nucleus is the site of transcription, it also contains avariety of proteins that either directly mediate transcription or areinvolved in regulating the process. These proteins includehelicases, which unwind the double-stranded DNA molecule tofacilitate access to it, RNA polymerases, which synthesize thegrowing RNA molecule, topoisomerases, which change theamount of supercoiling in DNA, helping it wind and unwind, aswell as a large variety of transcription factors that regulateexpression.

Processing of pre-mRNA

Newly synthesized mRNA molecules are known as primarytranscripts or pre-mRNA. They must undergo post-transcriptionalmodification in the nucleus before being exported to the

cytoplasm; mRNA that appears in the cytoplasm without these modifications is degraded rather than used for proteintranslation. The three main modifications are 5' capping, 3' polyadenylation, and RNA splicing. While in the nucleus,pre-mRNA is associated with a variety of proteins in complexes known as heterogeneous ribonucleoprotein particles(hnRNPs). Addition of the 5' cap occurs co-transcriptionally and is the first step in post-transcriptional modification.The 3' poly-adenine tail is only added after transcription is complete.

RNA splicing, carried out by a complex called the spliceosome, is the process by which introns, or regions of DNAthat do not code for protein, are removed from the pre-mRNA and the remaining exons connected to re-form a singlecontinuous molecule. This process normally occurs after 5' capping and 3' polyadenylation but can begin beforesynthesis is complete in transcripts with many exons. Many pre-mRNAs, including those encoding antibodies, canbe spliced in multiple ways to produce different mature mRNAs that encode different protein sequences. Thisprocess is known as alternative splicing, and allows production of a large variety of proteins from a limited amountof DNA.

Cell nucleus 43

Dynamics and regulation

Nuclear transport

Macromolecules, such as RNA and proteins, are actively transported across the nuclearmembrane in a process called the Ran-GTP nuclear transport cycle.

The entry and exit of large moleculesfrom the nucleus is tightly controlledby the nuclear pore complexes.Although small molecules can enterthe nucleus without regulation,macromolecules such as RNA andproteins require associationkaryopherins called importins to enterthe nucleus and exportins to exit."Cargo" proteins that must betranslocated from the cytoplasm to thenucleus contain short amino acidsequences known as nuclearlocalization signals, which are boundby importins, while those transportedfrom the nucleus to the cytoplasmcarry nuclear export signals bound byexportins. The ability of importins and exportins to transport their cargo is regulated by GTPases, enzymes thathydrolyze the molecule guanosine triphosphate to release energy. The key GTPase in nuclear transport is Ran, whichcan bind either GTP or GDP (guanosine diphosphate), depending on whether it is located in the nucleus or thecytoplasm. Whereas importins depend on RanGTP to dissociate from their cargo, exportins require RanGTP in orderto bind to their cargo.

Nuclear import depends on the importin binding its cargo in the cytoplasm and carrying it through the nuclear poreinto the nucleus. Inside the nucleus, RanGTP acts to separate the cargo from the importin, allowing the importin toexit the nucleus and be reused. Nuclear export is similar, as the exportin binds the cargo inside the nucleus in aprocess facilitated by RanGTP, exits through the nuclear pore, and separates from its cargo in the cytoplasm.Specialized export proteins exist for translocation of mature mRNA and tRNA to the cytoplasm afterpost-transcriptional modification is complete. This quality-control mechanism is important due to these molecules'central role in protein translation; mis-expression of a protein due to incomplete excision of exons ormis-incorporation of amino acids could have negative consequences for the cell; thus, incompletely modified RNAthat reaches the cytoplasm is degraded rather than used in translation.

Cell nucleus 44

Assembly and disassembly

An image of a newt lung cell stained with fluorescent dyesduring metaphase. The mitotic spindle can be seen, stained

green, attached to the two sets of chromosomes, stained lightblue. All chromosomes but one are already at the metaphase

plate.

During its lifetime, a nucleus may be broken down, either inthe process of cell division or as a consequence of apoptosis(the process of programmed cell death). During theseevents, the structural components of the nucleus — theenvelope and lamina — can be systematically degraded. Inmost cells, the disassembly of the nuclear envelope marksthe end of the prophase of mitosis. However, thisdisassembly of the nucleus is not a universal feature ofmitosis and does not occur in all cells. Some unicellulareukaryotes (e.g., yeasts) undergo so-called closed mitosis,in which the nuclear envelope remains intact. In closedmitosis, the daughter chromosomes migrate to oppositepoles of the nucleus, which then divides in two. The cells ofhigher eukaryotes, however, usually undergo open mitosis,which is characterized by breakdown of the nuclearenvelope. The daughter chromosomes then migrate toopposite poles of the mitotic spindle, and new nucleireassemble around them.

At a certain point during the cell cycle in open mitosis, the cell divides to form two cells. In order for this process tobe possible, each of the new daughter cells must have a full set of genes, a process requiring replication of thechromosomes as well as segregation of the separate sets. This occurs by the replicated chromosomes, the sisterchromatids, attaching to microtubules, which in turn are attached to different centrosomes. The sister chromatids canthen be pulled to separate locations in the cell. In many cells, the centrosome is located in the cytoplasm, outside thenucleus; the microtubules would be unable to attach to the chromatids in the presence of the nuclear envelope.Therefore the early stages in the cell cycle, beginning in prophase and until around prometaphase, the nuclearmembrane is dismantled. Likewise, during the same period, the nuclear lamina is also disassembled, a processregulated by phosphorylation of the lamins by protein kinases such as the CDC2 protein kinase. Towards the end ofthe cell cycle, the nuclear membrane is reformed, and around the same time, the nuclear lamina are reassembled bydephosphorylating the lamins.

However, in dinoflagellates, the nuclear envelope remains intact, the centrosomes are located in the cytoplasm, andthe microtubules come in contact with chromosomes, whose centromeric regions are incorporated into the nuclearenvelope (the so-called closed mitosis with extranuclear spindle). In many other protists (e.g., ciliates, sporozoans)and fungi, the centrosomes are intranuclear, and their nuclear envelope also does not disassemle during cell division.Apoptosis is a controlled process in which the cell's structural components are destroyed, resulting in death of thecell. Changes associated with apoptosis directly affect the nucleus and its contents, for example, in the condensationof chromatin and the disintegration of the nuclear envelope and lamina. The destruction of the lamin networks iscontrolled by specialized apoptotic proteases called caspases, which cleave the lamin proteins and, thus, degrade thenucleus' structural integrity. Lamin cleavage is sometimes used as a laboratory indicator of caspase activity in assaysfor early apoptotic activity. Cells that express mutant caspase-resistant lamins are deficient in nuclear changesrelated to apoptosis, suggesting that lamins play a role in initiating the events that lead to apoptotic degradation ofthe nucleus. Inhibition of lamin assembly itself is an inducer of apoptosis.The nuclear envelope acts as a barrier that prevents both DNA and RNA viruses from entering the nucleus. Some viruses require access to proteins inside the nucleus in order to replicate and/or assemble. DNA viruses, such as herpesvirus replicate and assemble in the cell nucleus, and exit by budding through the inner nuclear membrane. This

Cell nucleus 45

process is accompanied by disassembly of the lamina on the nuclear face of the inner membrane.

Disease-related dynamicsInitially, it has been suspected that immunoglobulins in general and autoantibodies in particular do not enter thenucleus. Now there is a body of evidence that under pathological conditions (e.g. lupus erythematosus) IgG can enterthe nucleus.[5]

Anucleated and multinucleated cells

Human red blood cells, like those of othermammals, lack nuclei. This occurs as anormal part of the cells' development.

Although most cells have a single nucleus, some eukaryotic cell types haveno nucleus, and others have many nuclei. This can be a normal process, as inthe maturation of mammalian red blood cells, or a result of faulty celldivision.

Anucleated cells contain no nucleus and are, therefore, incapable of dividingto produce daughter cells. The best-known anucleated cell is the mammalianred blood cell, or erythrocyte, which also lacks other organelles such asmitochondria, and serves primarily as a transport vessel to ferry oxygen fromthe lungs to the body's tissues. Erythrocytes mature through erythropoiesis inthe bone marrow, where they lose their nuclei, organelles, and ribosomes.The nucleus is expelled during the process of differentiation from anerythroblast to a reticulocyte, which is the immediate precursor of the matureerythrocyte. The presence of mutagens may induce the release of someimmature "micronucleated" erythrocytes into the bloodstream. Anucleatedcells can also arise from flawed cell division in which one daughter lacks anucleus and the other has two nuclei.

Multinucleated cells contain multiple nuclei. Most acantharean species of protozoa and some fungi in mycorrhizaehave naturally multinucleated cells. Other examples include the intestinal parasites in the genus Giardia, which havetwo nuclei per cell. In humans, skeletal muscle cells, called myocytes and syncytium, become multinucleated duringdevelopment; the resulting arrangement of nuclei near the periphery of the cells allows maximal intracellular spacefor myofibrils. Multinucleated and binucleated cells can also be abnormal in humans; for example, cells arising fromthe fusion of monocytes and macrophages, known as giant multinucleated cells, sometimes accompany inflammationand are also implicated in tumor formation.A number of dinoflagelates are known to have two nuclei.[6] Unlike other multinucleated cells these nuclei containtwo distinct lineages of DNA: one from the dinoflagelate and the other from a symbiotic diatom. Curiously themitochondrion and the plastid of the diatom remain functional.

EvolutionAs the major defining characteristic of the eukaryotic cell, the nucleus' evolutionary origin has been the subject ofmuch speculation. Four major hypotheses have been proposed to explain the existence of the nucleus, although nonehave yet earned widespread support.The first model known as the "syntrophic model" proposes that a symbiotic relationship between the archaea and bacteria created the nucleus-containing eukaryotic cell. (Organisms of the Archaea and Bacteria domain have no cell nucleus.[7]) It is hypothesized that the symbiosis originated when ancient archaea, similar to modern methanogenic archaea, invaded and lived within bacteria similar to modern myxobacteria, eventually forming the early nucleus. This theory is analogous to the accepted theory for the origin of eukaryotic mitochondria and chloroplasts, which are thought to have developed from a similar endosymbiotic relationship between proto-eukaryotes and aerobic bacteria.

Cell nucleus 46

The archaeal origin of the nucleus is supported by observations that archaea and eukarya have similar genes forcertain proteins, including histones. Observations that myxobacteria are motile, can form multicellular complexes,and possess kinases and G proteins similar to eukarya, support a bacterial origin for the eukaryotic cell.A second model proposes that proto-eukaryotic cells evolved from bacteria without an endosymbiotic stage. Thismodel is based on the existence of modern planctomycetes bacteria that possess a nuclear structure with primitivepores and other compartmentalized membrane structures. A similar proposal states that a eukaryote-like cell, thechronocyte, evolved first and phagocytosed archaea and bacteria to generate the nucleus and the eukaryotic cell.The most controversial model, known as viral eukaryogenesis, posits that the membrane-bound nucleus, along withother eukaryotic features, originated from the infection of a prokaryote by a virus. The suggestion is based onsimilarities between eukaryotes and viruses such as linear DNA strands, mRNA capping, and tight binding toproteins (analogizing histones to viral envelopes). One version of the proposal suggests that the nucleus evolved inconcert with phagocytosis to form an early cellular "predator". Another variant proposes that eukaryotes originatedfrom early archaea infected by poxviruses, on the basis of observed similarity between the DNA polymerases inmodern poxviruses and eukaryotes. It has been suggested that the unresolved question of the evolution of sex couldbe related to the viral eukaryogenesis hypothesis.A very recent proposal suggests that traditional variants of the endosymbiont theory are insufficiently powerful toexplain the origin of the eukaryotic nucleus. This model, termed the exomembrane hypothesis, suggests that thenucleus instead originated from a single ancestral cell that evolved a second exterior cell membrane; the interiormembrane enclosing the original cell then became the nuclear membrane and evolved increasingly elaborate porestructures for passage of internally synthesized cellular components such as ribosomal subunits.

Gallery

Comparison of human and chimpanzeechromosomes.

Mousechromosometerritories indifferent cell

types.

24 chromosometerritories inhuman cells.

References[1] Leeuwenhoek, A. van: Opera Omnia, seu Arcana Naturae ope exactissimorum Microscopiorum detecta, experimentis variis comprobata,

Epistolis ad varios illustres viros. J. Arnold et Delphis, A. Beman, Lugdinum Batavorum 1719–1730. Cited after: Dieter Gerlach, Geschichteder Mikroskopie. Verlag Harry Deutsch, Frankfurt am Main, Germany, 2009. ISBN 978-3-8171-1781-9.

[2] Online Version here (http:/ / www. t-cremer. de/ main_de/ cremer/ personen/ info_T_Cremer. htm#book)[3][3] PMID 1955462[4][4] PMID 15667322[5] Böhm I. IgG deposits can be detected in cell nuclei of patients with both lupus erythematosus and malignancy. Clin Rheumatol 2007;26(11)

1877-1882[6] Imanian B, Pombert JF, Dorrell RG, Burki F, Keeling PJ (2012) Tertiary endosymbiosis in two dinotoms has generated little change in the

mitochondrial genomes of their dinoflagellate hosts and diatom endosymbionts" PLoS One 7(8) e43763.[7] C.Michael Hogan. 2010. Archaea. eds. E.Monosson & C.Cleveland, Encyclopedia of Earth. National Council for Science and the

Environment, Washington DC. (http:/ / www. eoearth. org/ article/ Archaea?topic=49496)

Cell nucleus 47

Further reading

Library resources

About Cell nucleus

• Online books (http:/ / tools. wmflabs. org/ ftl/ cgi-bin/ ftl?st=& su=Cell+ nuclei& library=OLBP)• Resources in your library (http:/ / tools. wmflabs. org/ ftl/ cgi-bin/ ftl?st=& su=Cell+ nuclei)• Resources in other libraries (http:/ / tools. wmflabs. org/ ftl/ cgi-bin/ ftl?st=& su=Cell+ nuclei& library=0CHOOSE0)

• Goldman, Robert D.; Gruenbaum, Y; Moir, RD; Shumaker, DK; Spann, TP (2002). "Nuclear lamins: buildingblocks of nuclear architecture". Genes & Dev. 16 (5): 533–547. doi: 10.1101/gad.960502 (http:/ / dx. doi. org/ 10.1101/ gad. 960502). PMID  11877373 (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 11877373).

A review article about nuclear lamins, explaining their structure and various roles• Görlich, Dirk; Kutay, U (1999). "Transport between the cell nucleus and the cytoplasm". Ann. Rev. Cell Dev.

Biol. 15: 607–660. doi: 10.1146/annurev.cellbio.15.1.607 (http:/ / dx. doi. org/ 10. 1146/ annurev. cellbio. 15. 1.607). PMID  10611974 (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 10611974).

A review article about nuclear transport, explains the principles of the mechanism, and the various transportpathways

• Lamond, Angus I.; Earnshaw, WC (1998-04-24). "Structure and Function in the Nucleus". Science 280 (5363):547–553. doi: 10.1126/science.280.5363.547 (http:/ / dx. doi. org/ 10. 1126/ science. 280. 5363. 547). PMID 9554838 (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 9554838).

A review article about the nucleus, explaining the structure of chromosomes within the organelle, anddescribing the nucleolus and other subnuclear bodies

• Pennisi E. (2004). "Evolutionary biology. The birth of the nucleus". Science 305 (5685): 766–768. doi:10.1126/science.305.5685.766 (http:/ / dx. doi. org/ 10. 1126/ science. 305. 5685. 766). PMID  15297641 (http:/ /www. ncbi. nlm. nih. gov/ pubmed/ 15297641).

A review article about the evolution of the nucleus, explaining a number of different theories• Pollard, Thomas D.; William C. Earnshaw (2004). Cell Biology. Philadelphia: Saunders. ISBN 0-7216-3360-9.

A university level textbook focusing on cell biology. Contains information on nucleus structure and function,including nuclear transport, and subnuclear domains

External links• cellnucleus.com (http:/ / www. cellnucleus. com/ education_main. htm) Website covering structure and function

of the nucleus from the Department of Oncology at the University of Alberta.• http:/ / npd. hgu. mrc. ac. uk/ user/ ?page=compartment The Nuclear Protein Database] Information on nuclear

components.• The Nucleus Collection (http:/ / cellimages. ascb. org/ cdm4/ browse. php?CISOROOT=/ p4041coll6) in the

Image & Video Library (http:/ / cellimages. ascb. org/ ) of The American Society for Cell Biology (http:/ / www.ascb. org/ ) contains peer-reviewed still images and video clips that illustrate the nucleus.

• Nuclear Envelope and Nuclear Import Section (http:/ / cellimages. ascb. org/ u?/ p4041coll11,62) from LandmarkPapers in Cell Biology (http:/ / cellimages. ascb. org/ cdm4/ browse. php?CISOROOT=/ p4041coll11), Joseph G.Gall, J. Richard McIntosh, eds., contains digitized commentaries and links to seminal research papers on thenucleus. Published online in the Image & Video Library (http:/ / cellimages. ascb. org/ ) of The American Societyfor Cell Biology (http:/ / www. ascb. org/ )

• Cytoplasmic patterns generated by human antibodies (http:/ / www. antibodypatterns. com/ cytoplasmic. php)

Nucleolus 48

Nucleolus

The nucleolus is contained within the cell nucleus.

Cell biologyThe animal cell

Components of a typical animal cell:

1.1. Nucleolus2.2. Nucleus3. Ribosome (little dots)4.4. Vesicle5.5. Rough endoplasmic reticulum6. Golgi apparatus (or "Golgi body")7.7. Cytoskeleton8.8. Smooth endoplasmic reticulum9.9. Mitochondrion10.10. Vacuole11. Cytosol (fluid that contains organelles)12.12. Lysosome13.13. Centrosome14.14. Cell membrane

The nucleolus is a structure found in the nucleus of cells. It is made up of proteins and nucleic acids found in the nucleus of eukaryotic cells. Its function is to transcribe ribosomal RNA (rRNA) and combine it with proteins to form

Nucleolus 49

incomplete ribosomes.The nucleolus occupies up to about 25% of the volume of the cell nucleus. Malfunction of nucleoli can be the causeof several human diseases.[citation needed]

StructureThree major components of the nucleolus are recognized: the fibrillar centers (FC), the dense fibrillar components(DFC), and granular component (GC). The DFC or pars fibrosa consists of newly transcribed rRNA bound toribosomal proteins, while the GC, called pars granulosa, contains RNA bound to ribosomal proteins that arebeginning to assemble into ribosomes.However, it has been proposed that this particular organization is only observed in higher eukaryotes and that itevolved from a bipartite organization with the transition from anamniotes to amniotes. Reflecting the substantialincrease in the DNA intergenic region, an original fibrillar component would have separated into the FC and theDFC.[1]

Another structure identified within many nucleoli (particularly in plants) is a clear area in the center of the structurereferred to as a nucleolar vacuole. Nucleoli of various plant species have been shown to have very highconcentrations of iron in contrast to human and animal cell nucleoli.The nucleolus ultrastructure can be visualized through an electron microscope, while the organization and dynamicscan be studied through fluorescent protein tagging and fluorescent recovery after photobleaching (FRAP).Antibodies against the PAF49 protein can also be used as a marker for the nucleolus in immunofluorescenceexperiments.[2]

Function and ribosome assembly

Photomicrograph of nucleus and nucleolus

Nucleoli are formed around specific genetic loci callednucleolar organizing regions (NORs), first described byBarbara McClintock. Because of this non-random organization,the nucleolus is defined as a "genetically determinedelement."[3] A NOR is composed of tandem repeats of rRNAgenes, which can be found in several different chromosomes.The human genome, for example, contains more than 200clustered copies of the rRNA genes on five differentchromosomes (13, 14, 15, 21, 22). In a typical eukaryote andsometimes a prokaryote, an rRNA gene consists of a promoter,internal and external transcribed spacers (ITS/ETS), rRNAcoding sequences (18S, 5.8S, 28S) and an externalnon-transcribed spacer.

In ribosome biogenesis, two of the three eukaryotic RNApolymerases (pol I and III) are required, and these function in acoordinated manner. In an initial stage, the rRNA genes are transcribed as a single unit within the nucleolus by RNApol I or III. In order for this transcription to occur, several pol I-associated factors and DNA-specific transactingfactors are required. In yeast, the most important are: UAF (upstream activating factor), TBP (tata-box bindingprotein), and CF (core factor), which bind promoter elements and form the preinitiation complex (PIC), which is inturn recognized by RNA pol. In humans, a similar PIC is assembled with SLI, the promoter selectivity factor(composed of TBP and TBP-associated factors, or TAFs), IFs (transcription initiation factors) and UBF (upstream

Nucleolus 50

binding factor). RNA polymerase I transcribes most rRNA transcripts (28S, 18S, and 5.8S) but the 5S rRNA subunit(component of the 60S ribosomal subunit) is transcribed by RNA polymerase III.Transcription of the ribosomal gene yields a long precursor molecule (45S pre-rRNA) which still contains the ITSand ETS. Further processing is needed to generate the 18S RNA, 5.8S and 28S RNA molecules. In eukaryotes, theRNA-modifying enzymes are brought to their respective recognition sites by interaction with guide RNAs, whichbind these specific sequences. These guide RNAs belong to the class of small nucleolar RNAs (snoRNAs) which arecomplexed with proteins and exist as small-nucleolar-ribonucleoproteins (snoRNPs). Once the rRNA subunits areprocessed, they are ready to be assembled into larger ribosomal subunits. However, an additional rRNA molecule,the 5S rRNA, is also necessary. In yeast, the 5S rDNA sequence is localized in the external non-transcribed spacerand is transcribed in the nucleolus by RNA pol.In higher eukaryotes and plants, the situation is more complex, for the 5S DNA sequence lies outside the NOR and istranscribed by RNA pol III in the nucleoplasm, after which it finds its way into the nucleolus to participate in theribosome assembly. This assembly not only involves the rRNA, but ribosomal proteins as well. The genes encodingthese r-proteins are transcribed by pol II in the nucleoplasm by a "conventional" pathway of protein synthesis(transcription, pre-mRNA processing, nuclear export of mature mRNA and translation on cytoplasmic ribosomes).The mature r-proteins are then "imported" back into the nucleus and finally the nucleolus. Association andmaturation of rRNA and r-proteins result in the formation of the 40S (small) and 60S (large) subunits of thecomplete ribosome. These are exported through the nuclear pore complexes to the cytoplasm, where they remain freeor become associated with the endoplasmic reticulum, forming rough endoplasmic reticulum (RER).A continuous chain between the nucleoplasm and the inner parts of the nucleolus exists through a network ofnucleolar channels. In this way, macromolecules with a molecular weight up to 2000 kDa are easily distributedthroughout the nucleolus. [citation needed]

Sequestration of proteinsIn addition to its role in ribosomal biogenesis, the nucleolus is known to capture and immobilize proteins, a processknown as nucleolar sequestration. Proteins that are sequestered in the nucleolus are unable to diffuse and to interactwith their binding partners. Targets of this post-translational regulatory mechanism include VHL, PML, MDM2,RelA, HAND1 and hTERT, among many others. It is now known that long noncoding RNAs originating fromintergenic regions of the nucleolus are responsible for this phenomenon.

References[1] as PDF (http:/ / www. lafontainelab. com/ Suppl_data/ Thiry_2005/ S3. pdf)[2] PAF49 antibody | GeneTex Inc (http:/ / www. genetex. com/ PAF49-antibody-GTX102175. html). Genetex.com. Retrieved on 2013-03-03.[3] as PDF (http:/ / www. jic. ac. uk/ staff/ peter-shaw/ pdfs/ raska intrevcytol 06. pdf)

External links• Cooper, Geoffrey M. (2000). "The Nucleolus" (http:/ / www. ncbi. nlm. nih. gov/ books/ NBK9939/ ). The Cell: A

Molecular Approach (http:/ / www. ncbi. nlm. nih. gov/ books/ NBK9839/ ) (2nd ed.). Sunderland MA: SinauerAssociates. ISBN 0-87893-106-6.

• Nucleolus under electron microscope II at uni-mainz.de (http:/ / www. uni-mainz. de/ FB/ Medizin/ Anatomie/workshop/ EM/ EMNucleolus. html)

• Nuclear Protein Database – search under compartment (http:/ / npd. hgu. mrc. ac. uk/ user/compartment?page=nucleolus. html)

• Cell Nucleolus (http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Cell+ Nucleolus) at the USNational Library of Medicine Medical Subject Headings (MeSH)

• BU Histology Learning System: 20104loa (http:/ / www. bu. edu/ histology/ p/ 20104loa. htm)

Ribosome 51

Ribosome

The ribosome assembles polymeric protein molecules whose sequence is controlled bythe sequence of messenger RNA molecules. This is required by all living cells and

associated viruses.

The ribosome (from ribonucleic acidand the Greek soma, meaning "body")is a large and complex molecularmachine, found within all living cells,that serves as the primary site ofbiological protein synthesis(translation). Ribosomes link aminoacids together in the order specified bymessenger RNA (mRNA) molecules.Ribosomes consist of two majorsubunits—the small ribosomal subunitreads the mRNA, while the largesubunit joins amino acids to form apolypeptide chain. Each subunit iscomposed of one or more ribosomalRNA (rRNA) molecules and a varietyof proteins. The ribosomes andassociated molecules are also known as the translational apparatus.

The sequence of DNA encoding for a protein may be copied many times into messenger RNA (mRNA) chains of asimilar sequence. Ribosomes can bind to an mRNA chain and use it as a template for determining the correctsequence of amino acids in a particular protein. Amino acids are selected, collected and carried to the ribosome bytransfer RNA (tRNA molecules), which enter one part of the ribosome and bind to the messenger RNA chain. Theattached amino acids are then linked together by another part of the ribosome. Once the protein is produced, it canthen 'fold' to produce a specific functional three-dimensional structure.

A ribosome is made from complexes of RNAs and proteins and is therefore a ribonucleoprotein. Each ribosome isdivided into two subunits: the smaller subunit binds to the mRNA pattern, while the larger subunit binds to the tRNAand the amino acids. When a ribosome finishes reading an mRNA molecule, these two subunits split apart.Ribosomes are ribozymes, because the catalytic peptidyl transferase activity that links amino acids together isperformed by the ribosomal RNA.Ribosomes from bacteria, archaea and eukaryotes (the three domains of life on Earth) differ in their size, sequence,structure, and the ratio of protein to RNA. The differences in structure allow some antibiotics to kill bacteria byinhibiting their ribosomes, while leaving human ribosomes unaffected. In bacteria and archaea, more than oneribosome may move along a single mRNA chain at one time, each "reading" its sequence and producing acorresponding protein molecule. The ribosomes in the mitochondria of eukaryotic cells functionally resemble manyfeatures of those in bacteria, reflecting the likely evolutionary origin of mitochondria.

Ribosome 52

DiscoveryRibosomes were first observed in the mid-1950s by Romanian cell biologist George Emil Palade using an electronmicroscope as dense particles or granules for which, in 1974, he would win a Nobel Prize. The term "ribosome" wasproposed by scientist Richard B. Roberts in 1958:

During the course of the symposium a semantic difficulty became apparent. To some of the participants,"microsomes" mean the ribonucleoprotein particles of the microsome fraction contaminated by other proteinand lipid material; to others, the microsomes consist of protein and lipid contaminated by particles. The phrase“microsomal particles” does not seem adequate, and “ribonucleoprotein particles of the microsome fraction” ismuch too awkward. During the meeting, the word "ribosome" was suggested, which has a very satisfactoryname and a pleasant sound. The present confusion would be eliminated if “ribosome” were adopted todesignate ribonucleoprotein particles in sizes ranging from 35 to 100S.

— Roberts, R. B., Microsomal Particles and Protein Synthesis[1]

Albert Claude, Christian de Duve, and George Emil Palade were jointly awarded the Nobel Prize in Physiology orMedicine, in 1974, for the discovery of the ribosomes. The Nobel Prize in Chemistry 2009 was awarded toVenkatraman Ramakrishnan, Thomas A. Steitz and Ada E. Yonath for determining the detailed structure andmechanism of the ribosome.[2]

Structure

Figure 2 : Large (red) and small (blue) subunit fittogether

Ribosomes consist of two subunits that fit together (Figure 2) and workas one to translate the mRNA into a polypeptide chain during proteinsynthesis (Figure 1). Because they are formed from two subunits ofnon-equal size, they are slightly longer in the axis than in diameter.Prokaryotic ribosomes are around 20 nm (200 Å) in diameter and arecomposed of 65% ribosomal RNA and 35% ribosomal proteins.Eukaryotic ribosomes are between 25 and 30 nm (250–300 Å) indiameter and the ratio of rRNA to protein is close to 1. Bacterialsubunits consist of one or two and eukaryotic of one or three very largeRNA molecules (known as ribosomal RNA or rRNA) and multiple smaller protein molecules.Crystallographic workhas shown that there are no ribosomal proteins close to the reaction site for polypeptide synthesis. This proves thatthe protein components of ribosomes do not directly participate in peptide bond formation catalysis, but rathersuggests that these proteins act as a scaffold that may enhance the ability of rRNA to synthesize protein (See:Ribozyme).

Ribosome 53

Atomic structure of the 30S Subunit from Thermus thermophilus. Proteins are shown inblue and the single RNA chain in orange.

The ribosomal subunits of prokaryotesand eukaryotes are quite similar.[3]

The unit of measurement is theSvedberg unit, a measure of the rate ofsedimentation incentrifugation ratherthan size, and this accounts for whyfragment names do not add up (70S ismade of 50S and 30S).

Prokaryotes have 70S ribosomes, eachconsisting of a small (30S) and a large(50S) subunit. Their small subunit hasa 16S RNA subunit (consisting of 1540nucleotides) bound to 21 proteins. Thelarge subunit is composed of a 5SRNA subunit (120 nucleotides), a 23SRNA subunit (2900 nucleotides) and31 proteins. Affinity label for thetRNA binding sites on the E. coliribosome allowed the identification ofA and P site proteins most likelyassociated with the peptidyltransferaseactivity; labelled proteins are L27,L14, L15, L16, L2; at least L27 is located at the donor site, as shown by E. Collatz and A.P. Czernilofsky. Additionalresearch has demonstrated that the S1 and S21 proteins, in association with the 3'-end of 16S ribosomal RNA, areinvolved in the initiation of translation.

Eukaryotes have 80S ribosomes, each consisting of a small (40S) and large (60S) subunit. Their 40S subunit has an18S RNA (1900 nucleotides) and 33 proteins. The large subunit is composed of a 5S RNA (120 nucleotides), 28SRNA (4700 nucleotides), a 5.8S RNA (160 nucleotides) subunits and 46 proteins. During 1977, Czernilofskypublished research that used affinity labeling to identify tRNA-binding sites on rat liver ribosomes. Several proteins,including L32/33, L36, L21, L23, L28/29 and L13 were implicated as being at or near the peptidyl transferase center.The ribosomes found in chloroplasts and mitochondria of eukaryotes also consist of large and small subunits boundtogether with proteins into one 70S particle. These organelles are believed to be descendants of bacteria (seeEndosymbiotic theory) and as such their ribosomes are similar to those of bacteria.[4]

The various ribosomes share a core structure, which is quite similar despite the large differences in size. Much of theRNA is highly organized into various tertiary structural motifs, for example pseudoknots that exhibit coaxialstacking. The extra RNA in the larger ribosomes is in several long continuous insertions, such that they form loopsout of the core structure without disrupting or changing it.[3] All of the catalytic activity of the ribosome is carriedout by theRNA; the proteins reside on the surface and seem to stabilize the structure.The differences between the bacterial and eukaryotic ribosomes are exploited by pharmaceutical chemists to createantibiotics that can destroy a bacterial infection without harming the cells of the infected person. Due to thedifferences in their structures, the bacterial 70S ribosomes are vulnerable to these antibiotics while the eukaryotic80S ribosomes are not. Even though mitochondria possess ribosomes similar to the bacterial ones, mitochondria arenot affected by these antibiotics because they are surrounded by a double membrane that does not easily admit theseantibiotics into the organelle.[5]

Ribosome 54

High-resolution structure

Atomic structure of the 50S Subunit from Haloarcula marismortui. Proteins are shown inblue and the two RNA chains in orange and yellow. The small patch of green in the center

of the subunit is the active site.

The general molecular structure of theribosome has been known since theearly 1970s. In the early 2000s thestructure has been achieved at highresolutions, on the order of a few Å.

The first papers giving the structure ofthe ribosome at atomic resolution werepublished almost simultaneously inlate 2000. The 50S (large prokaryotic)subunit was determined from thearchaeons Haloarcula marismortui andDeinococcus radiodurans, and thestructure of the 30S subunit wasdetermined from Thermusthermophilus. These structural studieswere awarded the Nobel Prize inChemistry in 2009. Early the next year(May 2001) these coordinates wereused to reconstruct the entire T.thermophilus 70S particle at 5.5 Åresolution.

Two papers were published inNovember 2005 with structures of theEscherichia coli 70S ribosome. The structures of a vacant ribosome were determined at 3.5-Å resolution using x-raycrystallography. Then, two weeks later, a structure based on cryo-electron microscopy was published, which depictsthe ribosome at 11–15Å resolution in the act of passing a newly synthesized protein strand into theprotein-conducting channel.

The first atomic structures of the ribosome complexed with tRNA and mRNA molecules were solved by using X-raycrystallography by two groups independently, at 2.8 Å and at 3.7 Å. These structures allow one to see the details ofinteractions of the Thermus thermophilus ribosome with mRNA and with tRNAs bound at classical ribosomal sites.Interactions of the ribosome with long mRNAs containing Shine-Dalgarno sequences were visualized soon after thatat 4.5- to 5.5-Å resolution.In 2011, the first complete atomic structure of the eukaryotic 80S ribosome from the yeastSaccharomyces cerevisiaewas obtained by crystallography. The model reveals the architecture of eukaryote-specific elements and theirinteraction with the universally conserved core. At the same time, the complete model of a eukaryotic 40S ribosomalstructure in Tetrahymena thermophila was published and described the structure of the40S subunit as well as muchabout the 40S subunit's interaction with eIF1 during translation initiation. Similarly, the eukaryotic 60S subunitstructure was also determined from Tetrahymena thermophila in complex witheIF6.

Ribosome 55

FunctionRibosomes are the workhorses of protein biosynthesis, the process of translating mRNA into protein. The mRNAcomprises a series of codons that dictate to the ribosome the sequence of the amino acids needed to make the protein.Using the mRNA as a template, the ribosome traverses each codon (3 nucleotides) of the mRNA, pairing it with theappropriate amino acid provided by an aminoacyl-tRNA. aminoacyl-tRNA contains a complementary anticodon onone end and the appropriate amino acid on the other. The small ribosomal subunit, typically bound to anaminoacyl-tRNA containing the amino acid methionine, binds to an AUG codon on the mRNA and recruits the largeribosomal subunit. The ribosome contains three RNA binding sites, designated A, P and E. The A site binds anaminoacyl-tRNA; the P site binds a peptidyl-tRNA (a tRNA bound to the peptide being synthesized); and the E sitebinds a free tRNA before it exits the ribosome. Protein synthesis begins at a start codon AUG near the 5' end of themRNA. mRNA binds to the P site of the ribosome first. The ribosome is able to identify the start codon by use of theShine-Dalgarno sequence of the mRNA in prokaryotes and Kozak box in eukaryotes.Although catalysis of the peptide bond involves the C2 hydroxyl of RNA's P-site (see Function section below)adenosine in a protein shuttle mechanism, other steps in protein synthesis (such as translocation) are caused bychanges in protein conformations.Since their catalytic core is made of RNA, ribosomes are classified as"ribozymes,"and it is thought that they might be remnants of the RNA world.

Figure 3 : Translation of mRNA (1) by aribosome (2)(shown as small and large subunits)into a polypeptide chain (3). The ribosome begins

at the start codon of mRNA (AUG) and ends atthe stop codon (UAG).

In Figure 3, both ribosomal subunits (small and large) assemble at the start codon (towards the 5' end of the mRNA).The ribosome uses tRNA that matches the current codon (triplet) on the mRNA to append an amino acid to thepolypeptide chain. This is done for each triplet on the mRNA, while the ribosome moves towards the 3' end of themRNA. Usually in bacterial cells, several ribosomes are working parallel on a single mRNA, forming what is calledapolyribosome or polysome.

Ribosome locationsRibosomes are classified as being either "free" or "membrane-bound".Free and membrane-bound ribosomes differ only in their spatial distribution; they are identical in structure. Whetherthe ribosome exists in a free or membrane-bound state depends on the presence of an ER-targeting signal sequenceon the protein being synthesized, so an individual ribosome might be membrane-bound when it is making oneprotein, but free in the cytosol when it makes another protein.Ribosomes are sometimes referred to as organelles, but the use of the term organelle is often restricted to describingsub-cellular components that include a phospholipid membrane, which ribosomes, being entirely particulate, do not.For this reason, ribosomes may sometimes be described as "non-membranous organelles".

Ribosome 56

Free ribosomesFree ribosomes can move about anywhere in the cytosol, but are excluded from the cell nucleus and other organelles.Proteins that are formed from free ribosomes are released into the cytosol and used within the cell. Since the cytosolcontains high concentrations of glutathione and is, therefore, a reducing environment, proteins containing disulfidebonds, which are formed from oxidized cysteine residues, cannot be produced within it.

Membrane-bound ribosomesWhen a ribosome begins to synthesize proteins that are needed in some organelles, the ribosome making this proteincan become "membrane-bound". In eukaryotic cells this happens in a region of the endoplasmic reticulum (ER)called the "rough ER". The newly produced polypeptide chains are inserted directly into the ER by the ribosomeundertaking vectorial synthesis and are then transported to their destinations, through the secretory pathway. Boundribosomes usually produce proteins that are used within the plasma membrane or are expelled from the cell viaexocytosis.[6]

BiogenesisIn bacterial cells, ribosomes are synthesized in the cytoplasm through the transcription of multiple ribosome geneoperons. In eukaryotes, the process takes place both in the cell cytoplasm and in the nucleolus, which is a regionwithin the cell nucleus. The assembly process involves the coordinated function of over 200 proteins in the synthesisand processing of the four rRNAs, as well as assembly of those rRNAs with the ribosomal proteins.

References[1] Roberts, R. B., editor. (1958) "Introduction" in Microsomal Particles and Protein Synthesis. New York: Pergamon Press, Inc.[2] 2009 Nobel Prize in Chemistry (http:/ / nobelprize. org/ nobel_prizes/ chemistry/ laureates/ 2009/ ), Nobel Foundation.[3][3] The Molecular Biology of the Cell, fourth edition. Bruce Alberts, et al. Garland Science (2002) pg. 342 ISBN 0-8153-3218-1[4][4] The Molecular Biology of the Cell, fourth edition. Bruce Alberts, et al. Garland Science (2002) pg. 808 ISBN 0-8153-3218-1[5][5] O'Brien, T.W., The General Occurrence of 55S Ribosomes in Mammalian Liver Mitochondria. J. Biol. Chem., 245:3409 (1971).[6] http:/ / www. ncbi. nlm. nih. gov/ books/ NBK26841/ #A2204

External links• Lab computer simulates ribosome in motion (http:/ / news. com. com/ Lab+ computer+ simulates+ ribosome+ in+

motion/ 2100-11395_3-5907401. html)• Role of the Ribosome (http:/ / www. cytochemistry. net/ Cell-biology/ ribosome. htm), Gwen V. Childs, copied

here (http:/ / cellbio. utmb. edu/ cellbio/ ribosome. htm)• Ribosome (http:/ / www. proteopedia. org/ wiki/ index. php/ Ribosome) in Proteopedia (http:/ / www.

proteopedia. org) - The free, collaborative 3D encyclopedia of proteins & other molecules• Ribosomal proteins families in ExPASy (http:/ / www. expasy. org/ cgi-bin/ lists?ribosomp. txt)• Molecule of the Month (http:/ / www. pdb. org/ pdb/ static. do?p=education_discussion/ molecule_of_the_month/

index. html) © RCSB Protein Data Bank (http:/ / home. rcsb. org/ ):• Ribosome (http:/ / www. pdb. org/ pdb/ static. do?p=education_discussion/ molecule_of_the_month/ pdb10_1.

html)• Elongation Factors (http:/ / www. pdb. org/ pdb/ static. do?p=education_discussion/ molecule_of_the_month/

pdb81_1. html)• Palade (http:/ / www. faqs. org/ health/ bios/ 79/ George-Palade. html)

• 3D electron microscopy structures of ribosomes at the EM Data Bank(EMDB) (http:/ / www. pdbe. org/emsearch/ ribosome)

Ribosome 57

 This article incorporates public domain material from the NCBI document "Science Primer" (http:/ / www. ncbi.nlm. nih. gov/ About/ primer/ index. html).

Vesicle (biology and chemistry)

Scheme of a liposome formed by phospholipids in an aqueoussolution.

In cell biology, a vesicle is a small bubble within a cell,and thus a type of organelle. Enclosed by lipid bilayer,vesicles can form naturally, for example, duringendocytosis. Alternatively, they may be preparedartificially, in which case they are called liposomes. Ifthere is only one phospholipid bilayer, they are calledunilamellar vesicles; otherwise they are calledmultilamellar. The membrane enclosing the vesicle issimilar to that of the plasma membrane, and vesiclescan fuse with the plasma membrane to release theircontents outside of the cell. Vesicles can also fuse withother organelles within the cell.

Vesicles perform a variety of functions. Because it isseparated from the cytosol, the inside of the vesicle canbe made to be different from the cytosolic environment. For this reason, vesicles are a basic tool used by the cell fororganizing cellular substances. Vesicles are involved in metabolism, transport, buoyancy control, and enzymestorage. They can also act as chemical reaction chambers.

Sarfus image of lipid vesicles.

IUPAC definition

Closed structure formed by amphiphilic molecules thatcontains solvent (usually water).

The 2013 Nobel Prize in Physiology or Medicine wasshared by James Rothman, Randy Schekman, andThomas Südhof for their roles (building upon earlierresearch, some of it by their mentors) on the makeupand function of cell vesicles, especially in yeasts and inhumans, including information on each vesicle's partsand how they are assembled. When cell vesicles, whichhelp maintain a balance or equilibrium inside andoutside of the blood vessels and cells (between theintravascular and extravascular spaces and theintracellular and extracellular spaces, respectively),malfunction, potentially serious and often fatal conditions are the result. The dysfunction is thought to contribute toAlzheimer's disease, diabetes, some hard-to-treat cases of epilepsy, some cancers and immunological disorders, andcertain neurovascular conditions. These are likely either caused, influenced, or made worse, by the disorders of thecell vesicles.[1]

Vesicle (biology and chemistry) 58

Types of vesicles

Electron micrograph of a cell containing a food vacuole (fv) andtransport vacuole (TV) in a malaria parasite.

Vacuoles

Vacuoles are vesicles which contain mostly water.• Plant cells have a large central vacuole in the center

of the cell that is used for osmotic control andnutrient storage.

• Contractile vacuoles are found in certain protists,especially those in Phylum Ciliophora. Thesevacuoles take water from the cytoplasm and excreteit from the cell to avoid bursting due to osmoticpressure.

Lysosomes

• Lysosomes are involved in cellular digestion. Foodcan be taken from outside the cell into food vacuolesby a process called endocytosis. These foodvacuoles fuse with lysosomes which break down thecomponents so that they can be used in the cell. Thisform of cellular eating is called phagocytosis.

•• Lysosomes are also used to destroy defective or damaged organelles in a process called autophagy. They fusewith the membrane of the damaged organelle, digesting it.

Transport vesicles• Transport vesicles can move molecules between locations inside the cell, e.g., proteins from the rough

endoplasmic reticulum to the Golgi apparatus.• Membrane-bound and secreted proteins are made on ribosomes found in the rough endoplasmic reticulum. Most

of these proteins mature in the Golgi apparatus before going to their final destination which may be to lysosomes,peroxisomes, or outside of the cell. These proteins travel within the cell inside of transport vesicles.

Secretory vesiclesSecretory vesicles contain materials that are to be excreted from the cell. Cells have many reasons to excretematerials. One reason is to dispose of wastes. Another reason is tied to the function of the cell. Within a largerorganism, some cells are specialized to produce certain chemicals. These chemicals are stored in secretory vesiclesand released when needed.

Types of secretory vesicles

• Synaptic vesicles are located at presynaptic terminals in neurons and store neurotransmitters. When a signalcomes down an axon, the synaptic vesicles fuse with the cell membrane releasing the neurotransmitter so that itcan be detected by receptor molecules on the next nerve cell.

• In animals endocrine tissues release hormones into the bloodstream. These hormones are stored within secretoryvesicles. A good example is the endocrine tissue found in the islets of Langerhans in the pancreas. This tissuecontains many cell types that are defined by which hormones they produce.

Vesicle (biology and chemistry) 59

• Secretory vesicles hold the enzymes that are used to make the cell walls of plants, protists, fungi, bacteria, andArchaea cells as well as the extracellular matrix of animal cells.

Other types of vesicles• Gas vesicles are used by Archaea, bacteria and planktonic microorganisms, possibly to control vertical migration

by regulating the gas content and thereby buoyancy, or possibly to position the cell for maximum solar lightharvesting.

• Matrix vesicles are located within the extracellular space, or matrix. Using electron microscopy they werediscovered independently in 1967 by H. Clarke Anderson and Ermanno Bonucci. These cell-derived vesicles arespecialized to initiate biomineralisation of the matrix in a variety of tissues, including bone, cartilage, and dentin.During normal calcification, a major influx of calcium and phosphate ions into the cells accompanies cellularapoptosis (genetically determined self-destruction) and matrix vesicle formation. Calcium-loading also leads toformation of phosphatidylserine:calcium:phosphate complexes in the plasma membrane mediated in part by aprotein called annexins. Matrix vesicles bud from the plasma membrane at sites of interaction with theextracellular matrix. Thus, matrix vesicles convey to the extracellular matrix calcium, phosphate, lipids and theannexins which act to nucleate mineral formation. These processes are precisely coordinated to bring about, at theproper place and time, mineralization of the tissue's matrix unless the Golgi are non-existent.

• Multivesicular body, or MVB, is a membrane-bound vesicle containing a number of smaller vesicles.

Vesicle formation and transport

Cell biologyThe animal cell

Components of a typical animal cell:

1.1. Nucleolus2.2. Nucleus3. Ribosome (little dots)4.4. Vesicle5.5. Rough endoplasmic reticulum6. Golgi apparatus (or "Golgi body")7.7. Cytoskeleton8.8. Smooth endoplasmic reticulum9.9. Mitochondrion10.10. Vacuole11. Cytosol (fluid that contains organelles)12.12. Lysosome13.13. Centrosome14.14. Cell membrane

Vesicle (biology and chemistry) 60

Some vesicles are made when part of the membrane pinches off the endoplasmic reticulum or the Golgi complex.Others are made when an object outside of the cell is surrounded by the cell membrane.

Capturing cargo moleculesThe assembly of vesicles requires numerous coats to surround and bind to the proteins being transported; these bindto the coat vesicle. They also trap various transmembrane receptor proteins, called cargo receptors, which in turn trapthe cargo molecules.

Vesicle coatThe vesicle coat serves to sculpt the curvature of a donor membrane, and to select specific proteins as cargo. Itselects cargo proteins by binding to sorting signals. In this way the vesicle coat clusters selected membrane cargoproteins into nascent vesicle buds.There are three types of vesicle coats: clathrin, COPI, and COPII. Clathrin coats are found on vesicles traffickingbetween the Golgi and plasma membrane, the Golgi and endosomes, and the plasma membrane and endosomes.COPI coated vesicles are responsible for retrograde transport from the Golgi to the ER, while COPII coated vesiclesare responsible for anterograde transport from the ER to the Golgi.The clathrin coat is thought to assemble in response to regulatory G protein. A coatomer coat assembles anddisassembles due to an ADP ribosylation factor (ARF) protein.

Vesicle dockingSurface markers called SNAREs identify the vesicle's cargo, and complementary SNAREs on the target membraneact to cause fusion of the vesicle and target membrane. Such v-SNARES are hypothesised to exist on the vesiclemembrane, while the complementary ones on the target membrane are known as t-SNAREs.Often SNAREs associated with vesicles or target membranes are instead classified as Qa, Qb, Qc, or R SNAREsowing to further variation than simply v- or t-SNAREs. An array of different SNARE complexes can be seen indifferent tissues and subcellular compartments, with 36 isoforms currently identified in humans.Regulatory Rab proteins are thought to inspect the joining of the SNAREs. Rab protein is a regulatory GTP-bindingprotein, and controls the binding of these complementary SNAREs for a long enough time for the Rab protein tohydrolyse its bound GTP and lock the vesicle onto the membrane.

Vesicle fusionVesicle fusion can occur in one of two ways: full fusion or kiss-and-run fusion. Fusion requires the two membranesto be brought within 1.5 nm of each other. For this to occur water must be displaced from the surface of the vesiclemembrane. This is energetically unfavorable, and evidence suggests that the process requires ATP, GTP, andacetyl-coA, fusion is also linked to budding, which is why the term budding and fusing arises.

Vesicles in receptor downregulationMembrane proteins serving as receptors are sometimes tagged for downregulation by the attachment of ubiquitin.After arriving an endosome via the pathway described above, vesicles begin to form inside the endosome, takingwith them the membrane proteins meant for degradation; When the endosome either matures to become a lysosomeor is united with one, the vesicles are completely degraded. Without this mechanism, only the extracellular part ofthe membrane proteins would reach the lumen of the lysosome, and only this part would be degraded.It is because of these vesicles that the endosome is sometimes known as a multivesicular body. The pathway to theirformation is not completely understood; unlike the other vesicles described above, the outer surface of the vesicles isnot in contact with the cytosol.

Vesicle (biology and chemistry) 61

Vesicle preparation

Isolated vesicles

Producing membrane vesicles is one of the methods to investigate various membranes of the cell. After the livingtissue is crushed into suspension, various membranes form tiny closed bubbles. Big fragments of the crushed cellscan be later discarded by low speed centrifugation and later the fraction of the known origin (plasmalemma,tonoplast, etc.) can be isolated by precise high-speed centrifugation in the density gradient. Using osmotic shock, it ispossible temporarily open vesicles (filling in them with the required solution) and then centrifugate down again andresuspend in a different solution. Applying ionophores like valinomycin can create electrochemic gradients that arecomparable to the gradients inside the living cell.Vesicles are mainly used in two types of research:•• To find and later isolate membrane receptors that specifically bind hormones and various other important

substances.• To investigate transport of various ions or other substances across the membrane of the given type. While the

transport can be easier investigated with patch clamp techniques, vesicles can also be isolated from objects forthat the patch clamp is not applicable.

Artificial vesiclesPhospholipid vesicles have also been studied in biochemistry. For such studies, a homogeneous phospholipid vesiclesuspension can be prepared by sonication, injection of a phospholipid solution into the aqueous buffer solutionmembranes. In this way aqueous vesicle solutions can be prepared of different phospholipid composition, as well asdifferent sizes of vesicles.

References[1] 2013 Nobel Prize in Physiology or Medicine (http:/ / www. nobelprize. org/ nobel_prizes/ medicine/ laureates/ 2013/ press. html), press

release 2013-10-07

Further reading• Alberts, Bruce; et al. (1998). Molecular Biology of the Cell (Fourth ed.). New York: Garland.

ISBN 0-8153-2971-7.

External links• Lipids, Membranes and Vesicle Trafficking - The Virtual Library of Biochemistry and Cell Biology (http:/ /

www. biochemweb. org/ lipids_membranes. shtml)

Endoplasmic reticulum 62

Endoplasmic reticulum

Micrograph of rough endoplasmic reticulum network around the nucleus (shown inlower right-hand side of the picture). Dark small circles in the network are

mitochondria.

The endoplasmic reticulum (ER) is a typeof organelle in the cells of eukaryoticorganisms that forms an interconnectednetwork of flattened, membrane-enclosedsacs or tubes known as cisternae. Themembranes of the ER are continuous withthe outer membrane of the nuclear envelope.Endoplasmic reticulum occurs in most typesof eukaryotic cell but is absent from redblood cells and spermatozoa. There are twotypes of endoplasmic reticulum, roughendoplasmic reticulum (RER) and smoothendoplasmic reticulum (SER). The outer(cytosolic) face of the rough endoplasmicreticulum is studded with ribosomes that arethe sites of protein synthesis. Roughendoplasmic reticulum is especiallyprominent in cells such as hepatocyteswhere active protein synthesis occurs. The smooth endoplasmic reticulum lacks ribosomes and functions in lipidmetabolism, carbohydrate metabolism, and detoxification[citation needed] and is especially abundant in mammalianliver and gonad cells. The lacey membranes of the endoplasmic reticulum were first seen in 1945 by Keith R. Porter,Albert Claude, and Ernest F. Fullam.

Endoplasmic reticulum 63

Structure

1 Nucleus   2 Nuclear pore   3 Rough endoplasmic reticulum (RER)   4 Smoothendoplasmic reticulum (SER)   5 Ribosome on the rough ER   6 Proteins that are

transported   7 Transport vesicle   8 Golgi apparatus   9 Cis face of the Golgiapparatus   10 Trans face of the Golgi apparatus   11 Cisternae of the Golgi

apparatus

3D rendering of endoplasmic reticulum

The general structure of the endoplasmicreticulum is a membranous network ofcisternae (sac-like structures) held togetherby the cytoskeleton. The phospholipidmembrane encloses a space, the cisternalspace (or lumen), which is continuous withthe perinuclear space but separate from thecytosol. The functions of the endoplasmicreticulum can be summarized as thesynthesis and export of proteins andmembrane lipids, but varies between ER andcell type and cell function. The quantity ofRER and SER in a cell can slowlyinterchange from one type to the other,depending on the changing metabolicactivities of the cell. Transformation caninclude embedding of new proteins inmembrane as well as structural changes.Changes in protein content may occurwithout noticeable structural changes.[citation

needed]

Rough endoplasmic reticulum

The surface of the rough endoplasmicreticulum (often abbreviated RER) isstudded with protein-manufacturingribosomes giving it a "rough" appearance(hence its name). The binding site of theribosome on the rough endoplasmicreticulum is the translocon. However, theribosomes bound to it at any one time arenot a stable part of this organelle's structureas they are constantly being bound andreleased from the membrane. A ribosomeonly binds to the RER once a specificprotein-nucleic acid complex forms in thecytosol. This special complex forms when afree ribosome begins translating the mRNA of a protein destined for the secretory pathway. The first 5-30 aminoacids polymerized encode a signal peptide, a molecular message that is recognized and bound by a signal recognitionparticle (SRP). Translation pauses and the ribosome complex binds to the RER translocon where translationcontinues with the nascent protein forming into the RER lumen and/or membrane. The protein is processed in the ERlumen by an enzyme (a signal peptidase), which removes the signal peptide. Ribosomes at this point may be releasedback into the cytosol; however, non-translating ribosomes are also known to stay associated with translocons.

Endoplasmic reticulum 64

The membrane of the rough endoplasmic reticulum forms large double membrane sheets that are located near, andcontinuous with, the outer layer of the nuclear envelope. Although there is no continuous membrane between theendoplasmic reticulum and the Golgi apparatus, membrane-bound vesicles shuttle proteins between these twocompartments.[1] Vesicles are surrounded by coating proteins called COPI and COPII. COPII targets vesicles to theGolgi apparatus and COPI marks them to be brought back to the rough endoplasmic reticulum. The roughendoplasmic reticulum works in concert with the Golgi complex to target new proteins to their proper destinations. Asecond method of transport out of the endoplasmic reticulum involves areas called membrane contact sites, wherethe membranes of the endoplasmic reticulum and other organelles are held closely together, allowing the transfer oflipids and other small molecules.The rough endoplasmic reticulum is key in multiple functions:• Manufacture of lysosomal enzymes with a mannose-6-phosphate marker added in the cis-Golgi network[citation

needed]

• Manufacture of secreted proteins, either secreted constitutively with no tag or secreted in a regulatory mannerinvolving clathrin and paired basic amino acids in the signal peptide.

• Integral membrane proteins that stay embedded in the membrane as vesicles exit and bind to new membranes.Rab proteins are key in targeting the membrane; SNAP and SNARE proteins are key in the fusion event.

• Initial glycosylation as assembly continues. This is N-linked (O-linking occurs in the Golgi).• N-linked glycosylation: If the protein is properly folded, glycosyltransferase recognizes the AA sequence NXS

or NXT (with the S/T residue phosphorylated) and adds a 14-sugar backbone (2-N-acetylglucosamine,9-branching mannose, and 3-glucose at the end) to the side-chain nitrogen of Asn.

Smooth endoplasmic reticulumThe smooth endoplasmic reticulum (abbreviated SER) has functions in several metabolic processes. It synthesizeslipids, phospholipids, and steroids. Cells which secrete these products, such as those in the testes, ovaries, and skinoil glands have a great deal of smooth endoplasmic reticulum. It also carries out the metabolism of carbohydrates,drug detoxification, attachment of receptors on cell membrane proteins, and steroid metabolism. In muscle cells, itregulates calcium ion concentration. It is connected to the nuclear envelope. Smooth endoplasmic reticulum is foundin a variety of cell types (both animal and plant), and it serves different functions in each. The smooth endoplasmicreticulum also contains the enzyme glucose-6-phosphatase, which converts glucose-6-phosphate to glucose, a step ingluconeogenesis. It consists of tubules that are located near the cell periphery. These tubes sometimes branchforming a network that is reticular in appearance. In some cells, there are dilated areas like the sacs of roughendoplasmic reticulum. The network of smooth endoplasmic reticulum allows for an increased surface area to bedevoted to the action or storage of key enzymes and the products of these enzymes.[citation needed]

Sarcoplasmic reticulum

The sarcoplasmic reticulum (SR), from the Greek sarx, ("flesh"), is smooth ER found in smooth and striated muscle.The only structural difference between this organelle and the smooth endoplasmic reticulum is the medley ofproteins they have, both bound to their membranes and drifting within the confines of their lumens. Thisfundamental difference is indicative of their functions: The endoplasmic reticulum synthesizes molecules, while thesarcoplasmic reticulum stores and pumps calcium ions. The sarcoplasmic reticulum contains large stores of calcium,which it sequesters and then releases when the muscle cell is stimulated. It plays a major role inexcitation-contraction coupling.[citation needed]

Endoplasmic reticulum 65

FunctionsThe endoplasmic reticulum serves many general functions, including the folding of protein molecules in sacs calledcisternae and the transport of synthesized proteins in vesicles to the Golgi apparatus. Correct folding of newly madeproteins is made possible by several endoplasmic reticulum chaperone proteins, including protein disulfideisomerase (PDI), ERp29, the Hsp70 family member BiP/Grp78, calnexin, calreticulin, and the peptidylpropylisomerase family. Only properly folded proteins are transported from the rough ER to the Golgi apparatus.Disturbances in redox regulation, calcium regulation, glucose deprivation, and viral infection or the over-expressionof proteins can lead to endoplasmic reticulum stress (ER stress), a state in which the folding of proteins slows,leading to an increase in unfolded proteins. This stress is emerging as a potential cause of damage inhypoxia/ischemia, insulin resistance, and other disorders.[citation needed]

Protein transportSecretory proteins, mostly glycoproteins, are moved across the endoplasmic reticulum membrane. Proteins that aretransported by the endoplasmic reticulum throughout the cell are marked with an address tag called a signalsequence. The N-terminus (one end) of a polypeptide chain (i.e., a protein) contains a few amino acids that work asan address tag, which are removed when the polypeptide reaches its destination. Proteins that are destined for placesoutside the endoplasmic reticulum are packed into transport vesicles and moved along the cytoskeleton toward theirdestination.The endoplasmic reticulum is also part of a protein sorting pathway. It is, in essence, the transportation system of theeukaryotic cell. The majority of its resident proteins are retained within it through a retention motif. This motif iscomposed of four amino acids at the end of the protein sequence. The most common retention sequence is KDEL(lys-asp-glu-leu). However, variation on KDEL does occur and other sequences can also give rise to endoplasmicreticulum retention. It is not known whether such variation can lead to sub-ER localizations. There are three KDELreceptors in mammalian cells, and they have a very high degree of sequence identity. The functional differencesbetween these receptors remain to be established. [citation needed]

References[1] Endoplasmic reticulum. (n.d.). McGraw-Hill Encyclopedia of Science and Technology. Retrieved September 13, 2006, from Answers.com

Web site: http:/ / www. answers. com/ topic/ endoplasmic-reticulum

External links• Lipid and protein composition of Endoplasmic reticulum (http:/ / opm. phar. umich. edu/ atlas.

php?membrane=Endoplasmic reticulum membrane) in OPM database• Animations of the various cell functions referenced here (http:/ / multimedia. mcb. harvard. edu/ media. html)

Golgi apparatus 66

Golgi apparatus

Micrograph of Golgi apparatus, visible as a stack of semicircular black rings near thebottom. Numerous circular vesicles can be seen in proximity to the organelle.

The Golgi apparatus (/ˈɡoʊldʒiː/),also known as the Golgi complex,Golgi body, or simply the Golgi, is anorganelle found in most eukaryoticcells. It was identified in 1897 by theItalian physician Camillo Golgi andnamed after him in 1898.

Part of the cellular endomembranesystem, the Golgi apparatus packagesproteins inside the cell before they aresent to their destination; it isparticularly important in the processingof proteins for secretion.

Discovery

Owing to its large size, the Golgiapparatus was one of the firstorganelles to be discovered and observed in detail. It was discovered in 1898 by Italian physician Camillo Golgiduring an investigation of the nervous system. After first observing it under his microscope, he termed the structurethe internal reticular apparatus. Some doubted the discovery at first, arguing that the appearance of the structurewas merely an optical illusion created by the observation technique used by Golgi. With the development of modernmicroscopes in the 20th century, the discovery was confirmed. Early references to the Golgi referred to it by variousnames including the "Golgi–Holmgren apparatus", "Golgi–Holmgren ducts", and "Golgi–Kopsch apparatus". Theterm "Golgi apparatus" was used in 1910 and first appeared in scientific literature in 1913.

Golgi apparatus 67

Structure

Diagram of the Golgi apparatus

3D Rendering of Golgi Apparatus

Found within the cytoplasm of bothplant and animal cells, the Golgi iscomposed of stacks ofmembrane-bound structures known ascisternae (singular: cisterna). Anindividual stack is sometimes called adictyosome (from Greek dictyon: net +soma: body), especially in plant cells.A mammalian cell typically contains40 to 100 stacks. Between four andeight cisternae are usually present in astack; however, in some protists asmany as sixty have been observed.Each cisterna comprises a flat,membrane enclosed disc that includesspecial Golgi enzymes which modifyor help to modify cargo proteins thattravel through it.

The cisternae stack has four functionalregions: the cis-Golgi network,medial-Golgi, endo-Golgi, andtrans-Golgi network. Vesicles from theendoplasmic reticulum (via thevesicular-tubular clusters) fuse withthe network and subsequently progressthrough the stack to the trans Golginetwork, where they are packaged andsent to their destination. Each regioncontains different enzymes whichselectively modify the contentsdepending on where they reside. The cisternae also carry structural proteins important for their maintenance asflattened membranes which stack upon each other.

Function of a golgi bodyCells synthesize a large number of different macromolecules. The Golgi apparatus is integral in modifying, sorting,and packaging these macromolecules for cell secretion (exocytosis) or use within the cell. It primarily modifiesproteins delivered from the rough endoplasmic reticulum but is also involved in the transport of lipids around thecell, and the creation of lysosomes. In this respect it can be thought of as similar to a post office; it packages andlabels items which it then sends to different parts of the cell.Enzymes within the cisternae are able to modify the proteins by addition of carbohydrates (glycosylation) andphosphates (phosphorylation). In order to do so, the Golgi imports substances such as nucleotide sugars from thecytosol. These modifications may also form a signal sequence which determines the final destination of the protein.For example, the Golgi apparatus adds a mannose-6-phosphate label to proteins destined for lysosomes.

Golgi apparatus 68

The Golgi plays an important role in the synthesis of proteoglycans, which are molecules present in the extracellularmatrix of animals. It is also a major site of carbohydrate synthesis. This includes the production ofglycosaminoglycans (GAGs), long unbranched polysaccharides which the Golgi then attaches to a proteinsynthesised in the endoplasmic reticulum to form proteoglycans. Enzymes in the Golgi polymerize several of theseGAGs via a xylose link onto the core protein. Another task of the Golgi involves the sulfation of certain moleculespassing through its lumen via sulfotranferases that gain their sulfur molecule from a donor called PAPS. This processoccurs on the GAGs of proteoglycans as well as on the core protein. Sulfation is generally performed in thetrans-Golgi network. The level of sulfation is very important to the proteoglycans' signalling abilities as well asgiving the proteoglycan its overall negative charge.The phosphorylation of molecules requires that ATP is imported into the lumen of the Golgi and utilised by residentkinases such as casein kinase 1 and casein kinase 2. One molecule that is phosphorylated in the Golgi isApolipoprotein, which forms a molecule known as VLDL that is a constituent of blood serum. It is thought that thephosphorylation of these molecules is important to help aid in their sorting for secretion into the blood serum.The Golgi has a putative role in apoptosis, with several Bcl-2 family members localised there, as well as to themitochondria. A newly characterized protein, GAAP (Golgi anti-apoptotic protein), almost exclusively resides in theGolgi and protects cells from apoptosis by an as-yet undefined mechanism.

Vesicular transport

Diagram of secretory process from endoplasmic reticulum (orange) to Golgi apparatus(pink). 1. Nuclear membrane; 2. Nuclear pore; 3. Rough endoplasmic reticulum (RER);

4. Smooth endoplasmic reticulum (SER); 5. Ribosome attached to RER; 6.Macromolecules; 7. Transport vesicles; 8. Golgi apparatus; 9. Cis face of Golgi

apparatus; 10. Trans face of Golgi apparatus; 11. Cisternae of the Golgi Apparatus

The vesicles that leave the roughendoplasmic reticulum are transported tothe cis face of the Golgi apparatus, wherethey fuse with the Golgi membrane andempty their contents into the lumen.Once inside the lumen, the molecules aremodified, then sorted for transport totheir next destinations. The Golgiapparatus tends to be larger and morenumerous in cells that synthesize andsecrete large amounts of substances; forexample, the plasma B cells and theantibody-secreting cells of the immunesystem have prominent Golgi complexes.

Those proteins destined for areas of thecell other than either the endoplasmicreticulum or Golgi apparatus are movedtowards the trans face, to a complexnetwork of membranes and associatedvesicles known as the trans-Golginetwork (TGN). This area of the Golgi isthe point at which proteins are sorted andshipped to their intended destinations bytheir placement into one of at least threedifferent types of vesicles, dependingupon the molecular marker they carry.

Golgi apparatus 69

Types Description Example

Exocytoticvesicles

(continuous)

Vesicle contains proteins destined for extracellular release. After packaging, the vesicles bud off andimmediately move towards the plasma membrane, where they fuse and release the contents into theextracellular space in a process known as constitutive secretion.

Antibody release byactivated plasma B cells

Secretoryvesicles

(regulated)

Vesicle contains proteins destined for extracellular release. After packaging, the vesicles bud off andare stored in the cell until a signal is given for their release. When the appropriate signal is receivedthey move towards the membrane and fuse to release their contents. This process is known asregulated secretion.

Neurotransmitterrelease from neurons

Lysosomalvesicles

Vesicle contains proteins and ribosomes destined for the lysosome, an organelle of degradationcontaining many acid hydrolases, or to lysosome-like storage organelles. These proteins include bothdigestive enzymes and membrane proteins. The vesicle first fuses with the late endosome, and thecontents are then transferred to the lysosome via unknown mechanisms.

Digestive proteasesdestined for thelysosome

Transport mechanismThe transport mechanism which proteins use to progress through the Golgi apparatus is not yet clear; however anumber of hypotheses currently exist. Until recently, the vesicular transport mechanism was favoured but now moreevidence is coming to light to support cisternal maturation. The two proposed models may actually work inconjunction with each other, rather than being mutually exclusive. This is sometimes referred to as the combinedmodel.• Cisternal maturation model: the cisternae of the Golgi apparatus move by being built at the cis face and

destroyed at the trans face. Vesicles from the endoplasmic reticulum fuse with each other to form a cisterna at thecis face, consequently this cisterna would appear to move through the Golgi stack when a new cisterna is formedat the cis face. This model is supported by the fact that structures larger than the transport vesicles, such ascollagen rods, were observed microscopically to progress through the Golgi apparatus. This was initially apopular hypothesis, but lost favour in the 1980s. Recently it has made a comeback, as laboratories at theUniversity of Chicago and the University of Tokyo have been able to use new technology to directly observeGolgi compartments maturing. Additional evidence comes from the fact that COPI vesicles move in theretrograde direction, transporting endoplasmic reticulum proteins back to where they belong by recognizing asignal peptide.

• Vesicular transport model: Vesicular transport views the Golgi as a very stable organelle, divided intocompartments in the cis to trans direction. Membrane bound carriers transport material between the endoplasmicreticulum and the different compartments of the Golgi. Experimental evidence includes the abundance of smallvesicles (known technically as shuttle vesicles) in proximity to the Golgi apparatus. To direct the vesicles, actinfilaments connect packaging proteins to the membrane to ensure that they fuse with the correct compartment.

Golgi apparatus 70

Fate during mitosisIn animal cells, the Golgi apparatus will break up and disappear following the onset of mitosis, or cellular division.During the telophase of mitosis, the Golgi apparatus reappears. As of December 2009[1] it is uncertain how thisoccurs. In contrast, Golgi stacks have been observed to remain intact in plant or yeast cells throughout the cell cycle.The reason for this difference is not yet known, but it may, in part, be a consequence of golgin proteins.

References[1] http:/ / en. wikipedia. org/ w/ index. php?title=Golgi_apparatus& action=edit

Cytoskeleton

The eukaryotic cytoskeleton. Actin filaments are shown in red, microtubules ingreen, and the nuclei are in blue.

The cytoskeleton (also CSK) is a cellularscaffolding or skeleton contained within acell's cytoplasm. The cytoskeleton is presentin all cells; it was once thought to be uniqueto eukaryotes, but recent research hasidentified the prokaryotic cytoskeleton. Itforms structures such as flagella, cilia andlamellipodia and plays important roles inboth intracellular transport (the movementof vesicles and organelles, for example) andcellular division. In 1903 Nikolai K Koltsovproposed that the shape of cells wasdetermined by a network of tubules whichhe termed the cytoskeleton. The concept of aprotein mosaic that dynamically coordinatedcytoplasmic biochemistry was proposed byRudolph Peters in 1929 while the term(cytosquelette, in French) was firstintroduced by French embryologist PaulWintrebert in 1931.

Cytoskeleton 71

The Eukaryotic Cytoskeleton

Actin cytoskeleton of mouse embryo fibroblasts,stained with phalloidin.

Eukaryotic cells contain three main kinds of cytoskeletalfilaments, which are microfilaments, intermediate filaments, andmicrotubules. The cytoskeleton provides the cell with structureand shape, and by excluding macromolecules from some of thecytosol it adds to the level of macromolecular crowding in thiscompartment. Cytoskeletal elements interact extensively andintimately with cellular membranes. A number of small moleculecytoskeletal drugs have been discovered that interact with actinand microtubules. These compounds have proven useful instudying the cytoskeleton and several have clinical applications.

Microfilaments (actin filaments)

These are the thinnest filaments of the cytoskeleton. They are composed of linear polymers of actin subunits, andgenerate force by elongation at one end of the filament coupled with shrinkage at the other, causing net movement ofthe intervening strand. They also act as tracks for the movement of myosin molecules that attach to themicrofilament and "walk" along them. Actin structures are controlled by the Rho family of small GTP-bindingproteins such as Rho itself for contractile acto-myosin filaments ("stress fibers"), Rac for lamellipodia and Cdc42 forfilopodia.

Intermediate filaments

Microscopy of keratin filaments inside cells.

These filaments, averaging 10 nanometers in diameter, are morestable (strongly bound) than actin filaments, and heterogeneousconstituents of the cytoskeleton. Like actin filaments, theyfunction in the maintenance of cell-shape by bearing tension(microtubules, by contrast, resist compression. It may be useful tothink of micro- and intermediate filaments as cables, and ofmicrotubules as cellular support beams). Intermediate filamentsorganize the internal tridimensional structure of the cell, anchoringorganelles and serving as structural components of the nuclearlamina and sarcomeres. They also participate in some cell-cell andcell-matrix junctions.

Different intermediate filaments are:• made of vimentins, being the common structural support of

many cells.• made of keratin, found in skin cells, hair and nails.• neurofilaments of neural cells.• made of lamin, giving structural support to the nuclear envelope.

Cytoskeleton 72

Microtubules

Microtubules in a gel fixated cell.

Microtubules are hollow cylinders about 23 nm in diameter (lumen= approximately 15 nm in diameter), most commonly comprising13 protofilaments which, in turn, are polymers of alpha and betatubulin. They have a very dynamic behaviour, binding GTP forpolymerization. They are commonly organized by the centrosome.

In nine triplet sets (star-shaped), they form the centrioles, and innine doublets oriented about two additional microtubules(wheel-shaped) they form cilia and flagella. The latter formation iscommonly referred to as a "9+2" arrangement, where in eachdoublet is connected to another by the protein dynein. As bothflagella and cilia are structural components of the cell, and aremaintained by microtubules, they can be considered part of thecytoskeleton.

They play key roles in:• intracellular transport (associated with dyneins and kinesins, they transport organelles like mitochondria or

vesicles).• the axoneme of cilia and flagella.• the mitotic spindle.•• synthesis of the cell wall in plants.

Comparison

Cytoskeleton type[1] Diameter

(nm)Structure Subunit examples

Microfilaments 6 double helix actin

Intermediatefilaments

10 two anti-parallel helices/dimers, forming tetramers • vimentin (mesenchyme)• glial fibrillary acidic protein (glial

cells)• neurofilament proteins (neuronal

processes)• keratins (epithelial cells)•• nuclear lamins

Microtubules 23 protofilaments, in turn consisting of tubulin subunits in complexwith stathmin

α- and β-tubulin

The prokaryotic cytoskeletonThe cytoskeleton was previously thought to be a feature only of eukaryotic cells, but homologues to all the majorproteins of the eukaryotic cytoskeleton have recently been found in prokaryotes. Although the evolutionaryrelationships are so distant that they are not obvious from protein sequence comparisons alone, the similarity of theirthree-dimensional structures and similar functions in maintaining cell shape and polarity provides strong evidencethat the eukaryotic and prokaryotic cytoskeletons are truly homologous. However, some structures in the bacterialcytoskeleton may have yet to be identified.

Cytoskeleton 73

FtsZFtsZ was the first protein of the prokaryotic cytoskeleton to be identified. Like tubulin, FtsZ forms filaments in thepresence of GTP, but these filaments do not group into tubules. During cell division, FtsZ is the first protein to moveto the division site, and is essential for recruiting other proteins that synthesize the new cell wall between thedividing cells.

MreB and ParMProkaryotic actin-like proteins, such as MreB, are involved in the maintenance of cell shape. All non-sphericalbacteria have genes encoding actin-like proteins, and these proteins form a helical network beneath the cellmembrane that guides the proteins involved in cell wall biosynthesis.Some plasmids encode a partitioning system that involves an actin-like protein ParM. Filaments of ParM exhibitdynamic instability, and may partition plasmid DNA into the dividing daughter cells by a mechanism analogous tothat used by microtubules during eukaryotic mitosis.

CrescentinThe bacterium Caulobacter crescentus contains a 3rd protein, crescentin, that is related to the intermediate filamentsof eukaryotic cells. Crescentin is also involved in maintaining cell shape, such as helical and vibrioid forms ofbacteria, but the mechanism by which it does this is currently unclear.

History

MicrotrabeculaeA fourth eukaryotic cytoskeletal element, microtrabeculae, was proposed by Keith Porter based on images obtainedfrom high-voltage electron microscopy of whole cells in the 1970s. The images showed short, filamentous structuresof unknown molecular composition associated with known cytoplasmic structures. Porter proposed that thismicrotrabecular structure represented a novel filamentous network distinct from microtubules, filamentous actin, orintermediate filaments. It is now generally accepted that microtrabeculae are nothing more than an artifact of certaintypes of fixation treatment, although we have yet to fully understand the complexity of the cell's cytoskeleton.

References[1][1] Unless else specified in boxes, then ref is: Page 25

External links• Cytoskeleton, Cell Motility and Motors - The Virtual Library of Biochemistry and Cell Biology (http:/ / www.

biochemweb. org/ cytoskeleton. shtml)• Cytoskeleton database, clinical trials, recent literature, lab registry ... (http:/ / www. cytoskeletons. com)• Animation of leukocyte adhesion (http:/ / aimediaserver. com/ studiodaily/ videoplayer/ ?src=harvard/ harvard.

swf& width=640& height=520) (Animation with some images of actin and microtubule assembly and dynamics.)• http:/ / cellix. imba. oeaw. ac. at/ Cytoskeleton and cell motility including videos• Open access review article (http:/ / www. tandfonline. com/ doi/ full/ 10. 1080/ 00018732. 2013. 771509) on the

emergent complexity of the cytoskeleton (appeared in Advances in Physics, 2013)

Mitochondrion 74

Mitochondrion

Two mitochondria from mammalian lung tissue displaying their matrix and membranes asshown by electron microscopy

Cell biology

Components of a typical animal cell:

1.1. Nucleolus2.2. Nucleus3. Ribosome (little dots)4.4. Vesicle5.5. Rough endoplasmic reticulum6. Golgi apparatus (or "Golgi body")7.7. Cytoskeleton8.8. Smooth endoplasmic reticulum9.9. Mitochondrion10.10. Vacuole11. Cytosol (fluid that contains organelles)12.12. Lysosome13.13. Centrosome14.14. Cell membrane

Mitochondrion 75

Components of a typical mitochondrion 1 Outer membrane

1.1 Porin

2 Intermembrane space

2.1 Intracristal space

2.2 Peripheral space

3 Lamella

3.1 Inner membrane

3.11 Inner boundary membrane

3.12 Cristal membrane

3.2 Matrix

3.3 Cristæ

4 Mitochondrial DNA5 Matrix granule6 Ribosome7 ATP synthase

The mitochondrion (plural mitochondria) is a membrane-enclosed structure found in most eukaryotic cells (thecells that make up plants, animals, fungi, and many other forms of life). Mitochondria range from 0.5 to1.0 micrometer (μm) in diameter. These organelles are sometimes described as "cellular power plants" because theygenerate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. In additionto supplying cellular energy, mitochondria are involved in other tasks such as signaling, cellular differentiation, celldeath, as well as the control of the cell cycle and cell growth. Mitochondria have been implicated in several humandiseases, including mitochondrial disorders and cardiac dysfunction, and may play a role in the aging process. Theword mitochondrion comes from the Greek μίτος, mitos, i.e. "thread", and χονδρίον, chondrion, i.e. "granule".Several characteristics make mitochondria unique. The number of mitochondria in a cell varies widely by organismand tissue type. Many cells have only a single mitochondrion, whereas others can contain several thousandmitochondria. The organelle is composed of compartments that carry out specialized functions. These compartmentsor regions include the outer membrane, the intermembrane space, the inner membrane, and the cristae and matrix.Mitochondrial proteins vary depending on the tissue and the species. In humans, 615 distinct types of proteins havebeen identified from cardiac mitochondria, whereas in rats, 940 proteins have been reported. The mitochondrialproteome is thought to be dynamically regulated. Although most of a cell's DNA is contained in the cell nucleus, themitochondrion has its own independent genome. Further, its DNA shows substantial similarity to bacterial genomes.

Mitochondrion 76

HistoryThe first observations of intracellular structures that probably represent mitochondria were published in the 1840s.Richard Altmann, in 1894, established them as cell organelles and called them "bioblasts". The term "mitochondria"itself was coined by Carl Benda in 1898. Leonor Michaelis discovered that Janus green can be used as a supravitalstain for mitochondria in 1900. Friedrich Meves, in 1904, made the first recorded observation of mitochondria inplants (Nymphaea alba)[1] and in 1908, along with Claudius Regaud, suggested that they contain proteins and lipids.Benjamin F. Kingsbury, in 1912, first related them with cell respiration, but almost exclusively based onmorphological observations. In 1913 particles from extracts of guinea-pig liver were linked to respiration by OttoHeinrich Warburg, which he called "grana". Warburg and Heinrich Otto Wieland, who had also postulated a similarparticle mechanism, disagreed on the chemical nature of the respiration. It was not until 1925 when David Keilindiscovered cytochromes that the respiratory chain was described.In 1939 experiments using minced muscle cells demonstrated that one oxygen atom can form two adenosinetriphosphate molecules and in 1941 the concept of phosphate bonds being a form of energy in cellular metabolismwas developed by Fritz Albert Lipmann. In the following years the mechanism behind cellular respiration wasfurther elaborated, although its link to the mitochondria was not known. The introduction of tissue fractionation byAlbert Claude allowed mitochondria to be isolated from other cell fractions and biochemical analysis to beconducted on them alone. In 1946 he concluded that cytochrome oxidase and other enzymes responsible for therespiratory chain were isolated to the mitchondria. Over time the fractionation method was tweaked, improving thequality of the mitochondria isolated and other elements of cell respiration were determined to occur in themitochondria.The first high-resolution micrographs appeared in 1952, replacing the Janus Green stains as the preferred way ofvisualising the mitochondria. This led to a more detailed analysis of the structure of the mitochondria, includingconfirmation that they were surrounded by a membrane. It also showed a second membrane inside the mitochondriathat folded up in ridges dividing up the inner chamber and that the size and shape of the mitochondria varied fromcell to cell.The popular term "powerhouse of the cell" was coined by Philip Siekevitz in 1957.In 1967 it was discovered that mitochondria contained ribosomes. In 1968 methods were developed for mapping themitochondrial genes, with the genetic and physical map of yeast mitochondria being completed in 1976.

Mitochondrion 77

Structure

Mitochondrion ultrastructure (interactive diagram) A mitochondrion has a double membrane; the inner one contains itschemiosmotic apparatus and has deep grooves which increase its surface area. While commonly depicted as an "orange sausagewith a blob inside of it" (like it is here), mitochondria can take many shapes and their intermembrane space is quite thin.

Illustration depicting general mitochondrionstructure

A mitochondrion contains outer and inner membranes composed ofphospholipid bilayers and proteins. The two membranes have differentproperties. Because of this double-membraned organization, there arefive distinct parts to a mitochondrion. They are:

1.1. the outer mitochondrial membrane,2.2. the intermembrane space (the space between the outer and inner

membranes),3.3. the inner mitochondrial membrane,4.4. the cristae space (formed by infoldings of the inner membrane), and5.5. the matrix (space within the inner membrane).Mitochondria stripped of their outer membrane are called mitoplasts.

Outer membraneThe outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similarto that of the eukaryotic plasma membrane (about 1:1 by weight). It contains large numbers of integral proteinscalled porins. These porins form channels that allow molecules 5000 Daltons or less in molecular weight to freelydiffuse from one side of the membrane to the other. Larger proteins can enter the mitochondrion if a signalingsequence at their N-terminus binds to a large multisubunit protein called translocase of the outer membrane, whichthen actively moves them across the membrane. Disruption of the outer membrane permits proteins in theintermembrane space to leak into the cytosol, leading to certain cell death. The mitochondrial outer membrane canassociate with the endoplasmic reticulum (ER) membrane, in a structure called MAM (mitochondria-associatedER-membrane). This is important in the ER-mitochondria calcium signaling and involved in the transfer of lipidsbetween the ER and mitochondria.

Intermembrane spaceThe intermembrane space is the space between the outer membrane and the inner membrane. It is also known asperimitochondrial space. Because the outer membrane is freely permeable to small molecules, the concentrations ofsmall molecules such as ions and sugars in the intermembrane space is the same as the cytosol. However, largeproteins must have a specific signaling sequence to be transported across the outer membrane, so the proteincomposition of this space is different from the protein composition of the cytosol. One protein that is localized to theintermembrane space in this way is cytochrome c.

Mitochondrion 78

Inner membraneThe inner mitochondrial membrane contains proteins with five types of functions:1. Those that perform the redox reactions of oxidative phosphorylation2. ATP synthase, which generates ATP in the matrix3. Specific transport proteins that regulate metabolite passage into and out of the matrix4.4. Protein import machinery.5.5. Mitochondria fusion and fission protein.It contains more than 151 different polypeptides, and has a very high protein-to-phospholipid ratio (more than 3:1 byweight, which is about 1 protein for 15 phospholipids). The inner membrane is home to around 1/5 of the totalprotein in a mitochondrion. In addition, the inner membrane is rich in an unusual phospholipid, cardiolipin. Thisphospholipid was originally discovered in cow hearts in 1942, and is usually characteristic of mitochondrial andbacterial plasma membranes. Cardiolipin contains four fatty acids rather than two, and may help to make the innermembrane impermeable. Unlike the outer membrane, the inner membrane doesn't contain porins, and is highlyimpermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter or exitthe matrix. Proteins are ferried into the matrix via the translocase of the inner membrane (TIM) complex or viaOxa1. In addition, there is a membrane potential across the inner membrane, formed by the action of the enzymes ofthe electron transport chain.

Cristae

Cross-sectional image of cristae in rat liver mitochondrion todemonstrate the likely 3D structure and relationship to the inner

membrane

The inner mitochondrial membrane iscompartmentalized into numerous cristae, whichexpand the surface area of the inner mitochondrialmembrane, enhancing its ability to produce ATP. Fortypical liver mitochondria, the area of the innermembrane is about five times as large as the outermembrane. This ratio is variable and mitochondriafrom cells that have a greater demand for ATP, such asmuscle cells, contain even more cristae. These folds arestudded with small round bodies known as F1 particlesor oxysomes. These are not simple random folds butrather invaginations of the inner membrane, which canaffect overall chemiosmotic function.

One recent mathematical modeling study has suggestedthat the optical properties of the cristae in filamentous mitochondria may affect the generation and propagation oflight within the tissue.

MatrixThe matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in amitochondrion. The matrix is important in the production of ATP with the aid of the ATP synthase contained in theinner membrane. The matrix contains a highly concentrated mixture of hundreds of enzymes, special mitochondrialribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major functionsinclude oxidation of pyruvate and fatty acids, and the citric acid cycle.Mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins (see: protein biosynthesis). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 total genes: 22 tRNA, 2 rRNA, and 13 peptide genes. The 13 mitochondrial peptides in humans are integrated into the

Mitochondrion 79

inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus.

Mitochondria-associated ER membrane (MAM)The mitochondria-associated ER membrane (MAM) is another structural element that is increasingly recognized forits critical role in cellular physiology and homeostasis. Once considered a technical snag in cell fractionationtechniques, the alleged ER vesicle contaminants that invariably appeared in the mitochondrial fraction have beenre-identified as membranous structures derived from the MAM—the interface between mitochondria and the ER.Physical coupling between these two organelles had previously been observed in electron micrographs and has morerecently been probed with fluorescence microscopy. Such studies estimate that at the MAM, which may comprise upto 20% of the mitochondrial outer membrane, the ER and mitochondria are separated by a mere 10-25 nm and heldtogether by protein tethering complexes.Purified MAM from subcellular fractionation has shown to be enriched in enzymes involved in phospholipidexchange, in addition to channels associated with Ca2+ signaling. These hints of a prominent role for the MAM inthe regulation of cellular lipid stores and signal transduction have been borne out, with significant implications formitochondrial-associated cellular phenomena, as discussed below. Not only has the MAM provided insight into themechanistic basis underlying such physiological processes as intrinsic apoptosis and the propagation of calciumsignaling, but it also favors a more refined view of the mitochondria. Though often seen as static, isolated‘powerhouses’ hijacked for cellular metabolism through an ancient endosymbiotic event, the evolution of the MAMunderscores the extent to which mitochondria have been integrated into overall cellular physiology, with intimatephysical and functional coupling to the endomembrane system.

Phospholipid transfer

The MAM is enriched in enzymes involved in lipid biosynthesis, such as phosphatidylserine synthase on the ER faceand phosphatidylserine decarboxylase on the mitochondrial face. Because mitochondria are dynamic organellesconstantly undergoing fission and fusion events, they require a constant and well-regulated supply of phospholipidsfor membrane integrity. But mitochondria are not only a destination for the phospholipids they finish synthesis of;rather, this organelle also plays a role in inter-organelle trafficking of the intermediates and products of phospholipidbiosynthetic pathways, ceramide and cholesterol metabolism, and glycosphingolipid anabolism.Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediatesbetween organelles. In contrast to the standard vesicular mechanism of lipid transfer, evidence indicates that thephysical proximity of the ER and mitochondrial membranes at the MAM allows for lipid flipping between opposedbilayers. Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not requireATP. Instead, in yeast, it has been shown to be dependent on a multiprotein tethering structure termed theER-mitochondria encounter structure, or ERMES, although it remains unclear whether this structure directlymediates lipid transfer or is required to keep the membranes in sufficiently close proximity to lower the energybarrier for lipid flipping.The MAM may also be part of the secretory pathway, in addition to its role in intracellular lipid trafficking. Inparticular, the MAM appears to be an intermediate destination between the rough ER and the Golgi in the pathwaythat leads to very-low-density lipoprotein, or VLDL, assembly and secretion. The MAM thus serves as a criticalmetabolic and trafficking hub in lipid metabolism.

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Calcium signaling

A critical role for the ER in calcium signaling was acknowledged before such a role for the mitochondria was widelyaccepted, in part because the low affinity of Ca2+ channels localized to the outer mitochondrial membrane seemed tofly in the face of this organelle’s purported responsiveness to changes in intracellular Ca2+ flux. But the presence ofthe MAM resolves this apparent contradiction: the close physical association between the two organelles results inCa2+ microdomains at contact points that facilitate efficient Ca2+ transmission from the ER to the mitochondria.Transmission occurs in response to so-called “Ca2+ puffs” generated by spontaneous clustering and activation ofIP3R, a canonical ER membrane Ca2+ channel.The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca2+

waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake ofCa2+ by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to acertain degree from high Ca2+ exposure, the MAM often serves as a firewall that essentially buffers Ca2+ puffs byacting as a sink into which free ions released into the cytosol can be funneled. This Ca2+ tunneling occurs throughthe low-affinity Ca2+ receptor VDAC1, which recently has been shown to be physically tethered to the IP3R clusterson the ER membrane and enriched at the MAM. The ability of mitochondria to serve as a Ca2+ sink is a result of theelectrochemical gradient generated during oxidative phosphorylation, which makes tunneling of the cation anexergonic process.But transmission of Ca2+ is not unidirectional; rather, it is a two-way street. The properties of the Ca2+ pump SERCAand the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. Inparticular, clearance of Ca2+ by the MAM allows for spatio-temporal patterning of Ca2+ signaling because Ca2+

alters IP3R activity in a biphasic manner. SERCA is likewise affected by mitochondrial feedback: uptake of Ca2+ bythe MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca2+ forcontinued Ca2+ efflux at the MAM. Thus, the MAM is not a passive buffer for Ca2+ puffs; rather it helps modulatefurther Ca2+ signaling through feedback loops that affect ER dynamics.Regulating ER release of Ca2+ at the MAM is especially critical because only a certain window of Ca2+ uptakesustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca2+ signaling isrequired to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid cycle.However, once Ca2+ signaling in the mitochondria passes a certain threshold, it stimulates the intrinsic pathway ofapoptosis in part by collapsing the mitochondrial membrane potential required for metabolism. Studies examiningthe role of pro- and anti-apoptotic factors support this model; for example, the anti-apoptotic factor Bcl-2 has beenshown to interact with IP3Rs to reduce Ca2+ filling of the ER, leading to reduced efflux at the MAM and preventingcollapse of the mitochondrial membrane potential post-apoptotic stimuli. Given the need for such fine regulation ofCa2+ signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca2+ has been implicated in severalneurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are enriched at the MAM.

Molecular basis for tethering

Recent advances in the identification of the tethers between the mitochondrial and ER membranes suggest that the scaffolding function of the molecular elements involved is secondary to other, non-structural functions. In yeast, ERMES, a multiprotein complex of interacting ER- and mitochondrial-resident membrane proteins, is required for lipid transfer at the MAM and exemplifies this principle. One of its components, for example, is also a constituent of the protein complex required for insertion of transmembrane beta-barrel proteins into the lipid bilayer. However, a homologue of the ERMES complex has not been identified yet in mammalian cells. Other proteins implicated in scaffolding likewise have functions independent of structural tethering at the MAM; for example, ER-resident and mitochondrial-resident mitofusins form heterocomplexes that regulate the number of inter-organelle contact sites, although mitofusins were first identified for their role in fission and fusion events between individual mitochondria. Glucose-related protein 75 (grp75) is another dual-function protein. In addition to the matrix pool of grp75, a portion

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serves as a chaperone that physically links the mitochondrial and ER Ca2+ channels VDAC and IP3R for efficientCa2+ transmission at the MAM. Another potential tether is Sigma-1R, a non-opioid receptor whose stabilization ofER-resident IP3R may preserve communication at the MAM during the metabolic stress response.

Model of the yeast multimeric tethering complex,ERMES

Perspective

The MAM is a critical signaling, metabolic, and trafficking hub in thecell that allows for the integration of ER and mitochondrial physiology.Coupling between these organelles is not simply structural butfunctional as well and critical for overall cellular physiology andhomeostasis. The MAM thus offers a perspective on mitochondria thatdiverges from the traditional view of this organelle as a static, isolatedunit appropriated for its metabolic capacity by the cell. Instead, thismitochondrial-ER interface emphasizes the integration of themitochondria, the product of an endosymbiotic event, into diversecellular processes.

Organization and distributionMitochondria are found in nearly all eukaryotes.[2] They vary in number and location according to cell type. A singlemitochondrion is often found in unicellular organisms. Conversely, numerous mitochondria are found in human livercells, with about 1000–2000 mitochondria per cell, making up 1/5 of the cell volume. The mitochondrial content ofotherwise similar cells can vary substantially in size and membrane potential, with differences arising from sourcesincluding uneven partitioning at cell divisions, leading to extrinsic differences in ATP levels and downstreamcellular processes. The mitochondria can be found nestled between myofibrils of muscle or wrapped around thesperm flagellum. Often they form a complex 3D branching network inside the cell with the cytoskeleton. Theassociation with the cytoskeleton determines mitochondrial shape, which can affect the function as well. Recentevidence suggests that vimentin, one of the components of the cytoskeleton, is critical to the association with thecytoskeleton.

FunctionThe most prominent roles of mitochondria are to produce the energy currency of the cell, ATP (i.e., phosphorylationof ADP), through respiration, and to regulate cellular metabolism. The central set of reactions involved in ATPproduction are collectively known as the citric acid cycle, or the Krebs Cycle. However, the mitochondrion has manyother functions in addition to the production of ATP.

Energy conversionA dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the inner membrane for this task. This is done by oxidizing the major products of glucose, pyruvate, and NADH, which are produced in the cytosol. This process of cellular respiration, also known as aerobic respiration, is dependent on the presence of oxygen. When oxygen is limited, the glycolytic products will be metabolized by anaerobic fermentation, a process that is independent of the mitochondria. The production of ATP from glucose has an approximately 13-times higher yield during aerobic respiration compared to fermentation. Recently it has been shown that plant mitochondria can produce a limited amount of ATP without oxygen by using the alternate substrate

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nitrite.

Pyruvate and the citric acid cycle

Each pyruvate molecule produced by glycolysis is actively transported across the inner mitochondrial membrane,and into the matrix where it is oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH.The acetyl-CoA is the primary substrate to enter the citric acid cycle, also known as the tricarboxylic acid (TCA)cycle or Krebs cycle. The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exceptionof succinate dehydrogenase, which is bound to the inner mitochondrial membrane as part of Complex II. The citricacid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (threemolecules of NADH and one molecule of FADH2) that are a source of electrons for the electron transport chain, anda molecule of GTP (that is readily converted to an ATP).

NADH and FADH2: the electron transport chain

Diagram of the electron transport chain in the mitonchondrial intermembrane space

The redox energy from NADH and FADH2is transferred to oxygen (O2) in several stepsvia the electron transport chain. Theseenergy-rich molecules are produced withinthe matrix via the citric acid cycle but arealso produced in the cytoplasm byglycolysis. Reducing equivalents from thecytoplasm can be imported via themalate-aspartate shuttle system of antiporterproteins or feed into the electron transportchain using a glycerol phosphate shuttle.Protein complexes in the inner membrane(NADH dehydrogenase (ubiquinone), cytochrome c reductase, and cytochrome c oxidase) perform the transfer andthe incremental release of energy is used to pump protons (H+) into the intermembrane space. This process isefficient, but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species suchas superoxide. This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrialfunction associated with the aging process.

As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is establishedacross the inner membrane. The protons can return to the matrix through the ATP synthase complex, and theirpotential energy is used to synthesize ATP from ADP and inorganic phosphate (Pi). This process is calledchemiosmosis, and was first described by Peter Mitchell who was awarded the 1978 Nobel Prize in Chemistry for hiswork. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for theirclarification of the working mechanism of ATP synthase.

Heat production

Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. Thisprocess is known as proton leak or mitochondrial uncoupling and is due to the facilitated diffusion of protons intothe matrix. The process results in the unharnessed potential energy of the proton electrochemical gradient beingreleased as heat. The process is mediated by a proton channel called thermogenin, or UCP1. Thermogenin is a 33kDaprotein first discovered in 1973. Thermogenin is primarily found in brown adipose tissue, or brown fat, and isresponsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals, and is at its highest levelsin early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with age.

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Storage of calcium ions

Mitochondria (M) within a chondrocyte stained for calcium as shown by electronmicroscopy

The concentrations of free calcium in thecell can regulate an array of reactions and isimportant for signal transduction in the cell.Mitochondria can transiently store calcium,a contributing process for the cell'shomeostasis of calcium. In fact, their abilityto rapidly take in calcium for later releasemakes them very good "cytosolic buffers"for calcium.[3] The endoplasmic reticulum(ER) is the most significant storage site ofcalcium, and there is a significant interplaybetween the mitochondrion and ER withregard to calcium. The calcium is taken upinto the matrix by a calcium uniporter on the inner mitochondrial membrane. It is primarily driven by themitochondrial membrane potential. Release of this calcium back into the cell's interior can occur via asodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways. This can initiate calciumspikes or calcium waves with large changes in the membrane potential. These can activate a series of secondmessenger system proteins that can coordinate processes such as neurotransmitter release in nerve cells and releaseof hormones in endocrine cells.

Ca2+ influx to the mitochondrial matrix has recently been implicated as a mechanism to regulate respiratorybioenergetics by allowing the electrochemical potential across the membrane to transiently "pulse" fromΔΨ-dominated to pH-dominated, facilitating a reduction of oxidative stress.In neurons, concominant increases incytosolic and mitochondrial calcium act to synchronize neuronal activity with mitochondrial energy metabolism.Mitochondrial matrix calcium levels can reach the tens of micromolar levels, which is necessary for the activation ofisocitrate dehydrogenase, one of the key regulatory enzymes of the Kreb's cycle.

Additional functionsMitochondria play a central role in many other metabolic tasks, such as:• Signaling through mitochondrial reactive oxygen species• Regulation of the membrane potential• Apoptosis-programmed cell death•• Calcium signaling (including calcium-evoked apoptosis)• Regulation of cellular metabolism• Certain heme synthesis reactions (see also: porphyrin)• Steroid synthesis.Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in liver cellscontain enzymes that allow them to detoxify ammonia, a waste product of protein metabolism. A mutation in thegenes regulating any of these functions can result in mitochondrial diseases.

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Cellular proliferation regulationThe relationship between cellular proliferation and mitochondria has been investigated using cervical cancer Helacells. Tumor cells require an ample amount of ATP (Adenosine triphosphate) in order to synthesize bioactivecompounds such as lipids, proteins, and nucleotides for rapid cell proliferation. The majority of ATP in tumor cells isgenerated via the Oxidative Phosphorylation pathway (OxPhos). Interference with OxPhos have shown to cause cellcycle arrest suggesting that mitochondria plays a role in cell proliferation. Mitochondrial ATP production is alsovital for cell division in addition to other basic functions in the cell including the regulation of cell volume, soluteconcentration, and cellular architecture. ATP levels differ at various stages of the cell cycle suggesting that there is arelationship between the abundance of ATP and the cell's ability to enter a new cell cycle. ATP’s role in the basicfunctions of the cell make the cell cycle sensitive to changes in the availability of mitochondrial derived ATP. Thevariation in ATP levels at different stages of the cell cycle support the hypothesis that mitochondria plays animportant role in cell cycle regulation. Although the specific mechanisms between mitochondria and the cell cycleregulation is not well understood, studies have shown that low energy cell cycle checkpoints monitor the energycapability before committing to another round of cell division.

OriginThere are two hypotheses about the origin of mitochondria: endosymbiotic and autogenous. The endosymbiotichypothesis suggests mitochondria were originally prokaryotic cells, capable of implementing oxidative mechanismsthat were not possible to eukaryotic cells; they became endosymbionts living inside the eukaryote. In the autogenoushypothesis, mitochondria were born by splitting off a portion of DNA from the nucleus of the eukaryotic cell at thetime of divergence with the prokaryotes; this DNA portion would have been enclosed by membranes, which couldnot be crossed by proteins. Since mitochondria have many features in common with bacteria, the most accreditedtheory at present is endosymbiosis.[4]

A mitochondrion contains DNA, which is organized as several copies of a single, circular chromosome. Thismitochondrial chromosome contains genes for redox proteins such as those of the respiratory chain. The CoRRhypothesis proposes that this co-location is required for redox regulation. The mitochondrial genome codes for someRNAs of ribosomes, and the twenty-two tRNAs necessary for the translation of messenger RNAs into protein. Thecircular structure is also found in prokaryotes. The proto-mitochondrion was probably closely related to therickettsia. However, the exact relationship of the ancestor of mitochondria to the alpha-proteobacteria and whetherthe mitochondrion was formed at the same time or after the nucleus, remains controversial.A recent study by researchers of the University of Hawaiʻi at Mānoa and the Oregon State University indicates thatthe SAR11 clade of bacteria shares a relatively recent common ancestor with the mitochondria existing in mosteukaryotic cells.

Phylogeny of Rickettsiales

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Other alphaproteobacteria Rhodospirillales, Sphingomonadales, Rhodobacteraceae, Rhizobiales, etc.

Rickettsiales

SAR11 clade Pelagibacter ubique

Mitochondria

Anaplasmataceae

Ehrlichia

Anaplasma

Wolbachia

Neorickettsia

Rickettsiaceae Rickettsia

Robust phylogeny of Rickettsiales from Williams et al. (2007)

The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure. Theyclosely resemble the bacterial 70S ribosome and not the 80S cytoplasmic ribosomes, which are coded for by nuclearDNA.The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis. Theendosymbiotic hypothesis suggests that mitochondria descended from bacteria that somehow survived endocytosisby another cell, and became incorporated into the cytoplasm. The ability of these bacteria to conduct respiration inhost cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage.This symbiotic relationship probably developed 1.7 to 2 billion years ago.A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae.These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information,which once suggested that they appeared before the origin of mitochondria. However, this is now known to be anartifact of long-branch attraction—they are derived groups and retain genes or organelles derived from mitochondria(e.g., mitosomes and hydrogenosomes).

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Genome

Mitochondrial DNA.

The human mitochondrial genome is a circular DNA molecule of about16 kilobases. It encodes 37 genes: 13 for subunits of respiratorycomplexes I, III, IV and V, 22 for mitochondrial tRNA (for the 20standard amino acids, plus an extra gene for leucine and serine), and 2for rRNA. One mitochondrion can contain two to ten copies of itsDNA.

As in prokaryotes, there is a very high proportion of coding DNA andan absence of repeats. Mitochondrial genes are transcribed asmultigenic transcripts, which are cleaved and polyadenylated to yieldmature mRNAs. Not all proteins necessary for mitochondrial functionare encoded by the mitochondrial genome; most are coded by genes inthe cell nucleus and the corresponding proteins are imported into the mitochondrion. The exact number of genesencoded by the nucleus and the mitochondrial genome differs between species. Most mitochondrial genomes arecircular, although exceptions have been reported. In general, mitochondrial DNA lacks introns, as is the case in thehuman mitochondrial genome; however, introns have been observed in some eukaryotic mitochondrial DNA, such asthat of yeast and protists, including Dictyostelium discoideum.

In animals the mitochondrial genome is typically a single circular chromosome that is approximately 16 kb long andhas 37 genes. The genes, while highly conserved, may vary in location. Curiously, this pattern is not found in thehuman body louse (Pediculus humanus). Instead this mitochondrial genome is arranged in 18 minicircularchromosomes, each of which is 3–4 kb long and has one to three genes. This pattern is also found in other suckinglice, but not in chewing lice. Recombination has been shown to occur between the minichromosomes. The reason forthis difference is not known.While slight variations on the standard code had been predicted earlier,[5] none was discovered until 1979, whenresearchers studying human mitochondrial genes determined that they used an alternative code. Although, themitochondria of many other eukaryotes, including most plants, use the standard code.[6] Many slight variants havebeen discovered since,[7] including various alternative mitochondrial codes. Further, the AUA, AUC, and AUUcodons are all allowable start codons.

Exceptions to the universal genetic code (UGC) in mitochondria

Organism Codon Standard Mitochondria

Mammals AGA, AGG Arginine Stop codon

Invertebrates AGA, AGG Arginine Serine

Fungi CUA Leucine Threonine

All of the above AUA Isoleucine Methionine

UGA Stop codon Tryptophan

Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of RNAediting, which is common in mitochondria. In higher plants, it was thought that CGG encoded for tryptophan and notarginine; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with theuniversal genetic code for tryptophan. Of note, the arthropod mitochondrial genetic code has undergone parallelevolution within a phylum, with some organisms uniquely translating AGG to lysine.Mitochondrial genomes have far fewer genes than the bacteria from which they are thought to be descended. Although some have been lost altogether, many have been transferred to the nucleus, such as the respiratory complex

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II protein subunits. This is thought to be relatively common over evolutionary time. A few organisms, such as theCryptosporidium, actually have mitochondria that lack any DNA, presumably because all their genes have been lostor transferred. In Cryptosporidium, the mitochondria have an altered ATP generation system that renders the parasiteresistant to many classical mitochondrial inhibitors such as cyanide, azide, and atovaquone.

Replication and inheritanceMitochondria divide by binary fission, similar to bacterial cell division. The regulation of this division differsbetween eukaryotes. In many single-celled eukaryotes, their growth and division is linked to the cell cycle. Forexample, a single mitochondrion may divide synchronously with the nucleus. This division and segregation processmust be tightly controlled so that each daughter cell receives at least one mitochondrion. In other eukaryotes (inmammals for example), mitochondria may replicate their DNA and divide mainly in response to the energy needs ofthe cell, rather than in phase with the cell cycle. When the energy needs of a cell are high, mitochondria grow anddivide. When the energy use is low, mitochondria are destroyed or become inactive. In such examples, and incontrast to the situation in many single celled eukaryotes, mitochondria are apparently randomly distributed to thedaughter cells during the division of the cytoplasm. Understanding of mitochondrial dynamics, which is described asthe balance between mitochondrial fusion and fission, has revealed that functional and structural alterations inmitochondrial morphology are important factors in pathologies associated with several disease conditions.An individual's mitochondrial genes are not inherited by the same mechanism as nuclear genes. Typically, themitochondria are inherited from one parent only. In humans, when an egg cell is fertilized by a sperm, the eggnucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote nucleus. In contrast, themitochondria, and therefore the mitochondrial DNA, usually come from the egg only. The sperm's mitochondriaenter the egg but do not contribute genetic information to the embryo.[8] Instead, paternal mitochondria are markedwith ubiquitin to select them for later destruction inside the embryo.[9] The egg cell contains relatively fewmitochondria, but it is these mitochondria that survive and divide to populate the cells of the adult organism.Mitochondria are, therefore, in most cases inherited only from mothers, a pattern known as maternal inheritance.This mode is seen in most organisms including the majority of animals. However, mitochondria in some species cansometimes be inherited paternally. This is the norm among certain coniferous plants, although not in pine trees andyew trees. For Mytilidae mussels paternal inheritance only occurs within males of the species.[10] It has beensuggested that it occurs at a very low level in humans. There is a recent suggestion mitochondria that shorten malelifespan stay in the system because mitochondria are inherited only through the mother. By contrast natural selectionweeds out mitochondria that reduce female survival as such mitochondria are less likely to be passed on to the nextgeneration. Therefore it is suggested human females and female animals tend to live longer than males. The authorsclaim this is a partial explanation.[11]

Uniparental inheritance leads to little opportunity for genetic recombination between different lineages ofmitochondria, although a single mitochondrion can contain 2–10 copies of its DNA. For this reason, mitochondrialDNA usually is thought to reproduce by binary fission. What recombination does take place maintains geneticintegrity rather than maintaining diversity. However, there are studies showing evidence of recombination inmitochondrial DNA. It is clear that the enzymes necessary for recombination are present in mammalian cells.Further, evidence suggests that animal mitochondria can undergo recombination. The data are a bit morecontroversial in humans, although indirect evidence of recombination exists. If recombination does not occur, thewhole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying theevolutionary history of populations.

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Population genetic studiesThe near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information forscientists involved in population genetics and evolutionary biology. Because all the mitochondrial DNA is inheritedas a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can berepresented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations.The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide arecent date for mitochondrial Eve. This is often interpreted as strong support for a recent modern human expansionout of Africa. Another human example is the sequencing of mitochondrial DNA from Neanderthal bones. Therelatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and living humanshas been interpreted as evidence for lack of interbreeding between Neanderthals and anatomically modern humans.However, mitochondrial DNA reflects the history of only females in a population and so may not represent thehistory of the population as a whole. This can be partially overcome by the use of paternal genetic sequences, such asthe non-recombining region of the Y-chromosome. In a broader sense, only studies that also include nuclear DNAcan provide a comprehensive evolutionary history of a population.

Dysfunction and disease

Mitochondrial diseasesDamage and subsequent dysfunction in mitochondria is an important factor in a range of human diseases due to theirinfluence in cell metabolism. Mitochondrial disorders often present themselves as neurological disorders, but canmanifest as myopathy, diabetes, multiple endocrinopathy, or a variety of other systemic manifestations. Diseasescaused by mutation in the mtDNA include Kearns-Sayre syndrome, MELAS syndrome and Leber's hereditary opticneuropathy. In the vast majority of cases, these diseases are transmitted by a female to her children, as the zygotederives its mitochondria and hence its mtDNA from the ovum. Diseases such as Kearns-Sayre syndrome, Pearson'ssyndrome, and progressive external ophthalmoplegia are thought to be due to large-scale mtDNA rearrangements,whereas other diseases such as MELAS syndrome, Leber's hereditary optic neuropathy, myoclonic epilepsy withragged red fibers (MERRF), and others are due to point mutations in mtDNA.In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case inFriedreich's ataxia, hereditary spastic paraplegia, and Wilson's disease. These diseases are inherited in a dominancerelationship, as applies to most other genetic diseases. A variety of disorders can be caused by nuclear mutations ofoxidative phosphorylation enzymes, such as coenzyme Q10 deficiency and Barth syndrome. Environmentalinfluences may interact with hereditary predispositions and cause mitochondrial disease. For example, there may bea link between pesticide exposure and the later onset of Parkinson's disease. Other pathologies with etiologyinvolving mitochondrial dysfunction include schizophrenia, bipolar disorder, dementia, Alzheimer's disease,Parkinson's disease, epilepsy, stroke, cardiovascular disease, retinitis pigmentosa, and diabetes mellitus.Mitochondria-mediated oxidative stress plays a role in cardiomyopathy in Type 2 diabetics. Increased fatty acid delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in these cells. This process increases the reducing equivalents available to the electron transport chain of the mitochondria, ultimately increasing reactive oxygen species (ROS) production. ROS increases uncoupling proteins (UCPs) and potentiate proton leakage through the adenine nucleotide translocator (ANT), the combination of which uncouples the mitochondria. Uncoupling then increases oxygen consumption by the mitochondria, compounding the increase in fatty acid oxiation. This creates a vicious cycle of uncoupling; furthermore, even though oxygen consumption increases, ATP synthesis does not increase proportionally because the mitochondria is uncoupled. Less ATP availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile dysfunction. To compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction. The decreased

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intra-mitochondrial calcium concentration increases dehydrogenase activation and ATP synthesis. So in addition tolower ATP synthesis due to fatty acid oxidation, ATP synthesis is impaired by poor calcium signaling as well,causing cardiac problems for diabetics.

Possible relationships to agingGiven the role of mitochondria as the cell's powerhouse, there may be some leakage of the high-energy electrons inthe respiratory chain to form reactive oxygen species. This was thought to result in significant oxidative stress in themitochondria with high mutation rates of mitochondrial DNA (mtDNA). Hypothesized links between aging andoxidative stress are not new and were proposed over 60 years ago, which was later refined into the mitochondrialfree radical theory of aging. A vicious cycle was thought to occur, as oxidative stress leads to mitochondrial DNAmutations, which can lead to enzymatic abnormalities and further oxidative stress. However, recent measurements ofthe rate of accumulation of mutation observed in mitochondrial DNA[12] were estimated to be 1 mutation every 7884years (10^-7 to 10^-9 per base per year, dating back to the most recent common ancestor of humans and apes),consistent with other estimates of mutation rates of autosomal dna ( 10^-8 per base per generation[13])A number of changes can occur to mitochondria during the aging process. Tissues from elderly patients show adecrease in enzymatic activity of the proteins of the respiratory chain. However, mutated mtDNA can only be foundin about 0.2% of very old cells.[14] Large deletions in the mitochondrial genome have been hypothesized to lead tohigh levels of oxidative stress and neuronal death in Parkinson's disease. However, there is much debate overwhether mitochondrial changes are causes of aging or merely characteristics of aging. One notable study in micedemonstrated shortened lifespan but no increase in reactive oxygen species despite increasing mitochondrial DNAmutations. However, it has to be noted that aging non-mutant mice do not seem to accumulate a great number ofmutations in mitochondrial DNA imposing a cloud of doubt on the involvement of mitochondrial DNA mutations in"natural" aging. As a result, the exact relationships between mitochondria, oxidative stress, and aging have not yetbeen settled.

In popular cultureIn Madeleine L'Engle's A Wind in the Door, the Farandolae are fictional creatures that live inside mitochondria, anddo circular "dances" around their "trees of origin".In the Japanese novel Parasite Eve and the associated manga and video games, various characters are able tomanipulate the energies contained within their mitochondria, generating a wide array of effects on other livingcreatures.In the 2012 feature film The Bourne Legacy, the green pills taken by Aaron Cross (Jeremy Renner) contain a virusthat implants itself in the user's cells, increasing mitochondrial output.

References•  This article incorporates public domain material from the NCBI document "Science Primer" [15].[1][1] Ernster's citation is wrong, correct citation is , cited in Meves' 1908 paper and in , with confirmation of Nymphaea alba[2] The eukaryote Giardia lamblia, for example, does not contain mitochondria, but does have a mitochondiral-like gene, suggesting that it once

included either mitochondria or an endosymbiotic progenitor of it[3] Brighton, Carl T. and Robert M. Hunt (1978): "The role of mitochondria in growth plate calcification as demonstrated in a rachitic model",

Journal of Bone and Joint Surgery, 60-A: 630-639.[4][4] William F. Martin and Miklós Müller "Origin of mitochondria and hydrogenosomes", Springer Verlag, Heidelberg 2007.[5] Crick, F. H. C. and Orgel, L. E. (1973) "Directed panspermia." Icarus 19:341-346. p. 344: "It is a little surprising that organisms with

somewhat different codes do not coexist." (Further discussion at (http:/ / www. talkorigins. org/ faqs/ comdesc/ section1. html) )[6] NCBI "Mitochondrial Genetic Code in Taxonomy Tree" (http:/ / www. ncbi. nlm. nih. gov/ Taxonomy/ Utils/ wprintgc. cgi)[7] NCBI: "The Genetic Codes", Compiled by Andrzej (Anjay) Elzanowski and Jim Ostell (http:/ / 130. 14. 29. 110/ Taxonomy/ Utils/ wprintgc.

cgi?mode=c)

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[8] Kimball, J.W. (2006) "Sexual Reproduction in Humans: Copulation and Fertilization," (http:/ / home. comcast. net/ ~john. kimball1/BiologyPages/ S/ Sexual_Reproduction. html#Copulation_and_Fertilization) Kimball's Biology Pages (based on Biology, 6th ed., 1996)]

[9] Discussed in Science News (http:/ / www. sciencenews. org/ 20000101/ fob3. asp).[10] Male and Female Mitochondrial DNA Lineages in the Blue Mussel (Mytilus edulis) Species Group (http:/ / mbe. library. arizona. edu/ data/

1995/ 1205/ 3stew. pdf) by Donald T. Stewart, Carlos Saavedra, Rebecca R. Stanwood, Amy 0. Ball, and Eleftherios Zouros[11] Fruit flies offer DNA clue to why women live longer (http:/ / www. bbc. co. uk/ news/ health-19093442)[12] Soares et al, Correcting for Purifying Selection: An Improved Human Mitochondrial Molecular Clock (http:/ / www. ncbi. nlm. nih. gov/

pmc/ articles/ PMC2694979/ ?tool=pubmed) Am J Hum Genet. 2009 June 12; 84(6) 740–759.[13] Michael W. Nachman and Susan L. Crowell Estimate of the Mutation Rate per Nucleotide in Humans (http:/ / www. genetics. org/ content/

156/ 1/ 297. full) Genetics, Vol. 156, 297-304, September 2000[14] de Grey, Aubrey (Fall 2004). " Mitochondrial Mutations in Mammalian Aging: An Over-Hasty About-Turn? (http:/ / www. mprize. com/

files/ sens/ polg-PP. pdf)" Rejuvenation Res. 7 (3) 171–4. . PMID 15588517.[15] http:/ / www. ncbi. nlm. nih. gov/ About/ primer/ index. html

External links• Mitodb.com (http:/ / www. Mitodb. com) - The mitochondrial disease database.• Mitochondria Atlas (http:/ / www. uni-mainz. de/ FB/ Medizin/ Anatomie/ workshop/ EM/ EMMitoE. html) at

University of Mainz• Mitochondria Research Portal (http:/ / www. mitochondrial. net) at mitochondrial.net• Mitochondria: Architecture dictates function (http:/ / www. cytochemistry. net/ Cell-biology/ mitoch1. htm) at

cytochemistry.net• Mitochondria links (http:/ / bama. ua. edu/ ~hsmithso/ class/ bsc_495/ mito-plastids/ mito_web. html) at

University of Alabama• MIP (http:/ / www. mitophysiology. org/ ) Mitochondrial Physiology Society• 3D structures of proteins from inner mitochondrial membrane (http:/ / opm. phar. umich. edu/ localization.

php?localization=Mitochondrial inner membrane) at University of Michigan• 3D structures of proteins associated with outer mitochondrial membrane (http:/ / opm. phar. umich. edu/

localization. php?localization=Mitochondrial outer membrane) at University of Michigan• Mitochondrial Protein Partnership (http:/ / www. mitoproteins. org) at University of Wisconsin• MitoMiner - A mitochondrial proteomics database (http:/ / mitominer. mrc-mbu. cam. ac. uk) at MRC

Mitochondrial Biology Unit• Mitochondrion - Cell Centered Database (http:/ / ccdb. ucsd. edu/ sand/ main?stype=lite&

keyword=mitochondrion& Submit=Go& event=display& start=1)• Mitochondrion Reconstructed by Electron Tomography (http:/ / www. sci. sdsu. edu/ TFrey/ MitoMovie. htm) at

San Diego State University• Video Clip of Rat-liver Mitochondrion from Cryo-electron Tomography (http:/ / www. wadsworth. org/ databank/

electron/ cryomito_dis2. html)

Vacuole 91

Vacuole

Plant cell structure

Animal cell structure

A vacuole is a membrane-bound organellewhich is present in all plant and fungal cellsand some protist, animal[1] and bacterialcells. Vacuoles are essentially enclosedcompartments which are filled with watercontaining inorganic and organic moleculesincluding enzymes in solution, though incertain cases they may contain solids whichhave been engulfed. Vacuoles are formed bythe fusion of multiple membrane vesiclesand are effectively just larger forms ofthese.[2] The organelle has no basic shape orsize; its structure varies according to theneeds of the cell.

The function and significance of vacuolesvaries greatly according to the type of cell inwhich they are present, having much greaterprominence in the cells of plants, fungi andcertain protists than those of animals andbacteria. In general, the functions of thevacuole include:•• Isolating materials that might be harmful

or a threat to the cell•• Containing waste products•• Containing water in plant cells• Maintaining internal hydrostatic pressure

or turgor within the cell• Maintaining an acidic internal pH•• Containing small molecules•• Exporting unwanted substances from the cell•• Allows plants to support structures such as leaves and flowers due to the pressure of the central vacuole• In seeds, stored proteins needed for germination are kept in 'protein bodies', which are modified vacuoles.[3]

Vacuoles also play a major role in autophagy, maintaining a balance between biogenesis (production) anddegradation (or turnover), of many substances and cell structures in certain organisms. They also aid in the lysis andrecycling of misfolded proteins that have begun to build up within the cell. Thomas Boller [4] and others proposedthat the vacuole participates in the destruction of invading bacteria and Robert B Mellor proposed organ-specificforms have a role in 'housing' symbiotic bacteria. In protists, vacuoles have the additional function of storing foodwhich has been absorbed by the organism and assisting in the digestive and waste management process for the cell.The vacuole probably evolved several times independently, even within the Viridiplantae.[5]

Vacuole 92

BacteriaLarge vacuoles are found in three genera of filamentous sulfur bacteria, the Thioploca, Beggiatoa andThiomargarita. The cytosol is extremely reduced in these genera and the vacuole can occupy between 40–98% ofthe cell. The vacuole contains high concentrations of nitrate ions and is therefore thought to be a storage organelle.Gas vacuoles, which are freely permeable to gas, are present in some species of Cyanobacteria. They allow thebacteria to control their buoyancy.

Plants

The anthocyanin-storing vacuoles of Rhoeospathacea, a spiderwort, in cells that have

plasmolyzed

Most mature plant cells have one large vacuole that typically occupiesmore than 30% of the cell's volume, and that can occupy as much as80% of the volume for certain cell types and conditions.[6] Strands ofcytoplasm often run through the vacuole.

A vacuole is surrounded by a membrane called the tonoplast (wordorigin: Gk tón(os) + -o-, meaning “stretching”, “tension”, “tone” +comb. form repr. Gk plastós formed, molded). Also called thevacuolar membrane, the tonoplast is the cytoplasmic membranesurrounding a vacuole, separating the vacuolar contents from the cell'scytoplasm. As a membrane, it is mainly involved in regulating themovements of ions around the cell, and isolating materials that mightbe harmful or a threat to the cell.

Transport of protons from the cytosol to the vacuole stabilizescytoplasmic pH, while making the vacuolar interior more acidiccreating a proton motive force which the cell can use to transport nutrients into or out of the vacuole. The low pH ofthe vacuole also allows degradative enzymes to act. Although single large vacuoles are most common, the size andnumber of vacuoles may vary in different tissues and stages of development. For example, developing cells in themeristems contain small provacuoles and cells of the vascular cambium have many small vacuoles in the winter andone large one in the summer.

Aside from storage, the main role of the central vacuole is to maintain turgor pressure against the cell wall. Proteinsfound in the tonoplast (aquaporins) control the flow of water into and out of the vacuole through active transport,pumping potassium (K+) ions into and out of the vacuolar interior. Due to osmosis, water will diffuse into thevacuole, placing pressure on the cell wall. If water loss leads to a significant decline in turgor pressure, the cell willplasmolyze. Turgor pressure exerted by vacuoles is also required for cellular elongation: as the cell wall is partiallydegraded by the action of expansins, the less rigid wall is expanded by the pressure coming from within the vacuole.Turgor pressure exerted by the vacuole is also essential in supporting plants in an upright position. Another functionof a central vacuole is that it pushes all contents of the cell's cytoplasm against the cellular membrane, and thus keepsthe chloroplasts closer to light.[7] Most plants store chemicals in the vacuole that react with chemicals in the cytosol.If the cell is broken, for example by a herbivore, then the two chemicals can react forming toxic chemicals. In garlic,alliin and the enzyme alliinase are normally separated but form allicin if the vacuole is broken. A similar reaction isresponsible for the production of syn-propanethial-S-oxide when onions are cut.[citation needed]

Vacuole 93

FungiVacuoles in fungal cells perform similar functions to those in plants and there can be more than one vacuole per cell.In yeast cells the vacuole is a dynamic structure that can rapidly modify its morphology. They are involved in manyprocesses including the homeostasis of cell pH and the concentration of ions, osmoregulation, storing amino acidsand polyphosphate and degradative processes. Toxic ions, such as strontium (Sr2+

), cobalt(II) (Co2+

), and lead(II) (Pb2+

) are transported into the vacuole to isolate them from the rest of the cell.

AnimalsIn animal cells, vacuoles perform mostly subordinate roles, assisting in larger processes of exocytosis andendocytosis.Animal vacuoles are smaller than their plant counterparts but also usually greater in number.[8] There are also animalcells that do not have any vacuoles.[9]

Exocytosis is the extrusion process of proteins and lipids from the cell. These materials are absorbed into secretorygranules within the Golgi apparatus before being transported to the cell membrane and secreted into the extracellularenvironment. In this capacity, vacuoles are simply storage vesicles which allow for the containment, transport anddisposal of selected proteins and lipids to the extracellular environment of the cell.Endocytosis is the reverse of exocytosis and can occur in a variety of forms. Phagocytosis ("cell eating") is theprocess by which bacteria, dead tissue, or other bits of material visible under the microscope are engulfed by cells.The material makes contact with the cell membrane, which then invaginates. The invagination is pinched off, leavingthe engulfed material in the membrane-enclosed vacuole and the cell membrane intact. Pinocytosis ("cell drinking")is essentially the same process, the difference being that the substances ingested are in solution and not visible underthe microscope. Phagocytosis and pinocytosis are both undertaken in association with lysosomes which complete thebreakdown of the material which has been engulfed.Salmonella is able to survive and reproduce in the vacuoles of several mammal species after being engulfed.

References[1] Venes, Donald (2001). Taber's Cyclopedic Medical Dictionary (Twentieth Edition), (F.A. Davis Company, Philadelphia), p. 2287 ISBN

0-9762548-3-2.[2] Brooker, Robert J, et al. (2007). Biology (First Edition), (McGraw-Hill, New York), p. 79 ISBN 0-07-326807-0.[3] Matile, Phillipe (1993) Chapter 18: Vacuoles, discovery of lysosomal origin in Discoveries in Plant Biology: v. 1 (World Scientific

Publishing Co Pte Ltd)[4] Thomas Boller (http:/ / plantbiology. unibas. ch/ people/ boller/ boller. htm). Plantbiology.unibas.ch. Retrieved on 2011-09-02.[5] http:/ / www. uni-koeln. de/ math-nat-fak/ botanik/ bot1/ AGBecker/ Publikationen/ pdfs/ IRC2007. pdf[6] Alberts, Bruce, Johnson, Alexander, Lewis, Julian, Raff, Martin, Roberts, Keith, and Walter, Peter (2008). Molecular Biology of the Cell

(Fifth Edition), (Garland Science, New York), p. 781 ISBN 978-0-8153-4111-6.[7] Lincoln Taiz and Eduardo Zeiger Plant Physiology 3rd Edition SINAUER 2002 p.13 and 14 ISBN 0-87893-856-7[8] Differences Between Plant and Animal|Cell Procaryotic and Eucaryotic Cell (http:/ / www. icbse. org/ 2010/ 01/

differences-between-plant-and-animal-cell-procaryotic-and-eucaryotic-cell. html). iCBSE.org. 2011[9] Plant cells vs. Animal cells (http:/ / www. biology-online. org/ 11/ 1_plant_cells_vs_animal_cells. htm). Biology-Online.org

Lysosome 94

Lysosome

Cell biologyThe animal cell

Components of a typical animal cell:

1.1. Nucleolus2.2. Nucleus3. Ribosome (little dots)4.4. Vesicle5.5. Rough endoplasmic reticulum6. Golgi apparatus (or "Golgi body")7.7. Cytoskeleton8.8. Smooth endoplasmic reticulum9.9. Mitochondrion10.10. Vacuole11. Cytosol (fluid that contains organelles)12.12. Lysosome13.13. Centrosome14.14. Cell membrane

Lysosomes (derived from the Greek words lysis, meaning "to separate", and soma, "body") are the cell's wastedisposal system and can digest some compounds. They are used for the digestion of macromolecules fromphagocytosis (ingestion of other dying cells or larger extracellular material, like foreign invading microbes),endocytosis (where receptor proteins are recycled from the cell surface), and autophagy (wherein old or unneededorganelles or proteins, or microbes that have invaded the cytoplasm are delivered to the lysosome).Other functions include digesting bacteria (or other forms of waste) that invade a cell and helping repair damage tothe plasma membrane by serving as a membrane patch, sealing the wound. In the past, lysosomes were thought tokill cells that are no longer wanted, such as those in the tails of tadpoles or in the web from the fingers of a 3- to6-month-old fetus.

DiscoveryChristian de Duve, then chairman of the Laboratory of Physiological Chemistry at the Catholic University of Louvain in Belgium, had been studying the mechanism of action of a pancreatic hormone insulin in liver cells. By 1949 he and his team had focussed on the enzyme called glucose 6-phosphatase, which is the first crucial enzyme in sugar metabolism and the target of insulin. They already suspected that this enzyme played a key role in regulating blood sugar levels. However, even after a series of experiments, they failed to purify and isolate the enzyme from the cellular extracts. Therefore they tried a more arduous procedure of cell fractionation, by which cellular components are separated based on their sizes using centrifugation. They succeeded in detecting the enzyme activity from the

Lysosome 95

microsomal fraction. This was the crucial step in the serendipitous discovery. To estimate the enzyme activity, theyused that of standardised enzyme acid phosphatase, and found that the activity was quite low (10% of the expectedvalue). One day, the enzyme activity of purified cell fractions which had been refrigerated for five days wasmeasured. Surprisingly the enzyme activity was increased to normal of that of the fresh sample. The result was thesame no matter how many times they repeated the estimation. This led to the conclusion that a membrane-like barrierlimited the accessibility of the enzyme to its substrate, so that the enzymes were able to diffuse after a few days.They described the membrane-like barrier as a "saclike structure surrounded by a membrane and containing acidphosphatase." It became obvious that an unrelated enzyme from the cell fraction came from a membranous fractionswhich were definitely cell organelles, and in 1955 De Duve named them "lysosomes" to reflect their digestiveproperties. That same year, Alex B. Novikoff from the University of Vermont visited de Duve´s laboratory, andsucessfully obtained the first electron micrographs of the new organelle. Using a staining method for acidphosphatase, de Duve and Novikoff confirmed the location of the hydrolytic enzymes of lysosomes using light andelectron microscopic studies. de Duve won the Nobel Prize in Physiology or Medicine in 1974 for this discovery.

Function and structureLysosomes are cellular organelles that contain acid hydrolase enzymes that break down waste materials and cellulardebris. They can be described as the stomach of the cell. They are found in animal cells, while their existence inyeasts and plants is disputed. Some biologists say the same roles are performed by lytic vacuoles, while otherssuggest there is strong evidence that lysosomes are indeed found in some plant cells. Lysosomes digest excess orworn-out organelles, food particles, and engulf viruses or bacteria. The membrane around a lysosome allows thedigestive enzymes to work at the pH they require. Lysosomes fuse with autophagic vacuoles and dispense theirenzymes into the autophagic vacuoles, digesting their contents. They are frequently nicknamed "suicide-bags" or"suicide-sacs" by cell biologists due to their autolysis. A group of genetic inherited disorders called lysosomalstorage diseases (LSD) results from the dysfunction of lysosomes.The size of a lysosome varies from 0.1–1.2 μm. At pH 4.8, the interior of the lysosomes is acidic compared to theslightly basic cytosol (pH 7.2). The lysosome maintains this pH differential by pumping protons (H+ ions) from thecytosol across the membrane via proton pumps and chloride ion channels. The lysosomal membrane protects thecytosol, and therefore the rest of the cell, from the degradative enzymes within the lysosome. The cell is additionallyprotected from any lysosomal acid hydrolases that drain into the cytosol, as these enzymes are pH-sensitive and donot function well or at all in the alkaline environment of the cytosol.This ensures that cytosolic molecules andorganelles are not lysed in case there is leakage of the hydrolytic enzymes from the lysosome.

FormationMany components of animal cells are recycled by transferring them inside or embedded in sections of membrane.For instance, in endocytosis, a portion of the cell’s plasma membrane pinches off to form a vesicle that willeventually fuse with an organelle within the cell. Without active replenishment, the plasma membrane wouldcontinuously decrease in size. It is thought that lysosomes participate in this dynamic membrane exchange systemand are formed by a gradual maturation process from endosomes.The production of lysosomal proteins suggests one method of lysosome sustainment. Lysosomal protein genes aretranscribed in the nucleus. mRNA transcripts exit the nucleus into the cytosol, where they are translated byribosomes. The nascent peptide chains are translocated into the rough endoplasmic reticulum, where they aremodified. Upon exiting the endoplasmic reticulum and entering the Golgi apparatus via vesicular transport, a specificlysosomal tag, mannose 6-phosphate, is added to the peptides. The presence of these tags allow for binding tomannose 6-phosphate receptors in the Golgi apparatus, a phenomenon that is crucial for proper packaging intovesicles destined for the lysosomal system.

Lysosome 96

Upon leaving the Golgi apparatus, the lysosomal enzyme-filled vesicle fuses with a late endosome, a relativelyacidic organelle with an approximate pH of 5.5. This acidic environment causes dissociation of the lysosomalenzymes from the mannose 6-phosphate receptors. The enzymes are packed into vesicles for further transport toestablished lysosomes. The late endosome itself can eventually grow into a mature lysosome, as evidenced by thetransport of endosomal membrane components from the lysosomes back to the endosomes.

LysosomotropismWeak bases with lipophilic properties accumulate in acidic intracellular compartments like lysosomes. While theplasma and lysosomal membranes are permeable for neutral and uncharged species of weak bases, the chargedprotonated species of weak bases do not permeate biomembranes and accumulate within lysosomes. Theconcentration within lysosomes may reach levels 100 to 1000 fold higher than extracellular concentrations. Thisphenomenon is called "lysosomotropism" or "acid trapping". The amount of accumulation of lysosomotropiccompounds may be estimated using a cell based mathematical model.A significant part of the clinically approved drugs are lipophilic weak bases with lysosomotropic properties. Thisexplains a number of pharmacological properties of these drugs, such as high tissue-to-blood concentration gradientsor long tissue elimination half-lifes; these properties have been found for drugs such as haloperidol,levomepromazine, and amantadine. However, high tissue concentrations and long elimination half-lives areexplained also by lipophilicity and absorption of drugs to fatty tissue structures. Important lysosomal enzymes, suchas acid sphingomyelinase, may be inhibited by lysososomally accumulated drugs. Such compounds are termedFIASMAs (functional inhibitor of acid sphingomyelinase) and include for example fluoxetine, sertraline, oramitriptyline.

References

External links•  This article incorporates public domain material from the NCBI document "Science Primer" (http:/ / www.

ncbi. nlm. nih. gov/ About/ primer/ index. html).• 3D structures of proteins associated with lysosome membrane (http:/ / opm. phar. umich. edu/ localization.

php?localization=Lysosome membrane)• Hide and Seek Foundation For Lysosomal Research Team (http:/ / www. hideandseek. org)• Self-Destructive Behavior in Cells May Hold Key to a Longer Life (http:/ / www. nytimes. com/ 2009/ 10/ 06/

science/ 06cell. html)• Mutations in the Lysosomal Enzyme–Targeting Pathway and Persistent Stuttering (http:/ / content. nejm. org/ cgi/

content/ full/ NEJMoa0902630)• Animation showing how lysosomes are made, and their function (http:/ / highered. mcgraw-hill. com/ olc/ dl/

120067/ bio01. swf)

Centrosome 97

Centrosome

The structure of the centrosome

Cell biologyThe animal cell

Components of a typical animal cell:

1.1. Nucleolus2.2. Nucleus3. Ribosome (little dots)4.4. Vesicle5.5. Rough endoplasmic reticulum6. Golgi apparatus (or "Golgi body")7.7. Cytoskeleton8.8. Smooth endoplasmic reticulum9.9. Mitochondrion10.10. Vacuole11. Cytosol (fluid that contains organelles)12.12. Lysosome13.13. Centrosome14.14. Cell membrane

In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center (MTOC) of the animal cell as well as a regulator of cell-cycle progression. It was discovered by Edouard Van Beneden in 1883. and

Centrosome 98

was described and named in 1888 by Theodor Boveri. The centrosome is thought to have evolved only in themetazoan lineage of eukaryotic cells. Fungi and plants use other MTOC structures to organize their microtubules.Although the centrosome has a key role in efficient mitosis in animal cells, it is not essential.Centrosomes are composed of two orthogonally arranged centrioles surrounded by an amorphous mass of proteintermed the pericentriolar material (PCM). The PCM contains proteins responsible for microtubule nucleation andanchoring including γ-tubulin, pericentrin and ninein. In general, each centriole of the centrosome is based on a ninetriplet microtubule assembled in a cartwheel structure, and contains centrin, cenexin and tektin.

Roles of the centrosome

Role of the centrosome in cell cycle progression

Centrosomes are associated with the nuclearmembrane during prophase of the cell cycle.In mitosis the nuclear membrane breaksdown and the centrosome nucleatedmicrotubules (parts of the cytoskeleton) caninteract with the chromosomes to build themitotic spindle.

The mother centriole, the older of the two inthe centriole pair, also has a central role inmaking cilia and flagella.

The centrosome is copied only once per cellcycle so that each daughter cell inherits onecentrosome, containing two structures calledcentrioles (see also: centrosome cycle). Thecentrosome replicates during the S phase ofthe cell cycle. During the prophase in theprocess of cell division called mitosis, thecentrosomes migrate to opposite poles of the cell. The mitotic spindle then forms between the two centrosomes.Upon division, each daughter cell receives one centrosome. Aberrant numbers of centrosomes in a cell have beenassociated with cancer. Doubling of a centrosome is similar to DNA replication in two respects: thesemiconservative nature of the process and the action of cdk2 as a regulator of the process. But the processes areessentially different in that centrosome doubling does not occur by template reading and assembly. The mothercentriole just aids in the accumulation of materials required for the assembly of the daughter centriole.

Centrosome 99

Centrosome (shown by arrow) next to nucleus

Interestingly, centrioles are notrequired for the progression of mitosis.When the centrioles are irradiated by alaser, mitosis proceeds normally with amorphologically normal spindle.Moreover, development of the fruit flyDrosophila is largely normal whencentrioles are absent due to a mutationin a gene required for their duplication.In the absence of the centrioles themicrotubules of the spindle are focusedby motors allowing the formation of abipolar spindle. Many cells cancompletely undergo interphase withoutcentrioles. Unlike centrioles, centrosomes are required for survival of the organism. Acentrosomal cells lack radialarrays of astral microtubules. They are also defective in spindle positioning and in ability to establish a centrallocalization site in cytokinesis. The function of centrosome in this context is hypothesized to ensure the fidelity ofcell division because it greatly increases the efficacy. Some cell types arrest in the following cell cycle whencentrosomes are absent. This is not a universal phenomenon.

When the nematode C. elegans egg is fertilized the sperm delivers a pair of centrioles. These centrioles will form thecentrosomes which will direct the first cell division of the zygote and this will determine its polarity. It's not yet clearwhether the role of the centrosome in polarity determination is microtubule dependent or independent.

Centrosome alterations in cancer cellsTheodor Boveri, in 1914, described centrosome aberrations in cancer cells. This initial observation was subsequentlyextended to many types of human tumors. Centrosome alterations in cancer can be divided in two subgroups,structural or numeric aberrations, yet both can be simultaneously found in a tumor.

Structural aberrationsUsually they appear due to uncontrolled expression of centrosome components, or due to post-translationalmodifications (such as phosphorylations) which are not adequate for those components. These modifications mayproduce variations in centrosome size (usually too big, due to an excess of pericentriolar material). On top of this,due to the fact that centrosomal proteins have the tendency to form aggregates, often centrosome-related bodies(CRBs) are observed in ectopic places. Both enlarged centrosomes and CRBs are similar to the centrosomalstructures observed in tumors,. Even more, these structures can be induced in culture cells by overexpression ofspecific centrosomal proteins, such as CNap-1 or Nlp. These structures may look very similar, yet detailed studiesreveal that they may present very different properties, depending on their proteic composition. For instance, theircapacity to incorporate γ-TuRC complexes (see also: γ-tubulin) can be very variable, and so their capacity tonucleate microtubules, therefore affecting in different way the shape, polarity and motility of implicated tumor cells.

Centrosome 100

Numeric aberrationsThe presence of an inadequate number of centrosomes is very often linked to the apparition of genome instabilityand the loss of tissular differentiation. However, the method to count the centrosome number (each one with 2centrioles) is often not very precise, because it is frequently assesed using fluorescence microscopy, whoseresolution capacity is not the best. Nevertheless, it is clear that the presence of supernumerary (in excess)centrosomes is a common event in human tumors. It has been observed that loss of the tumor-suppressor protein p53produces supernumerary centrosomes, as well as deregulation of other proteins implicated in tumorigenesis inhumans, such as BRCA1 and BRCA2 (for references, see ). It is important to note that supernumerary centrosomescan be generated by very different mechanisms: specific reduplication of the centrosome, failure during cell division(generating an increase in chromosome number), cell fusion (for instance due to infection by specific viruses) or denovo generation of centrosomes. At this point there is not sufficient information to know how frequent are thosemechanisms in vivo, but it is possible that the increase in centrosome numbers due a failure during cell divisionmight be more frequent than appreciated, because many "primary" defects in one cell (deregulation of the cell cycle,defective DNA or chromatin metabolism, failure in the spindle checkpoint, etc...) would generate a failure in celldivision, an increase in ploidy and an increase in centrosome numbers as a "secondary" effect.

Evolution of the centrosomeThe evolutionary history of the centrosome and the centriole has been traced for some of the signature genes, e.g. thecentrins. Centrins participate in calcium signaling and are required for centriole duplication. There exist two mainsubfamilies of centrins, both of which are present in the early-branching eukaryote Giardia intestinalis. Centrinshave therefore been present in the common ancestor of eukaryotes. Conversely, they have no recognizable homologsin archea and bacteria and are thus part of the "eukaryotic signature genes." Although there are studies on theevolution of the centrins and centrioles, no studies have been published on the evolution of the pericentriolarmaterial.It is evident that some parts of the centrosome are highly diverged in the model species Drosophila melanogasterand Caenorhabditis elegans. For example, both species have lost one of the centrin subfamilies that are usuallyassociated with centriole duplication. Drosophila melanogaster mutants that lack centrosomes can even develop tomorphologically normal adult flies, which then die shortly after birth because their sensory neurons lack cilia. Thus,these flies have evolved functionally redundant machinery, which is independent of the centrosomes.

Centrosome associated nucleotidesResearch in 2006 indicated that centrosomes from Surf clam eggs contain RNA sequences. The sequences identifiedwere found in "few to no" other places in the cell, and do not appear in existing genome databases. One identifiedRNA sequence contains a putative RNA polymerase, leading to the hypothesis of an RNA based genome within thecentrosome. However, subsequent research has shown that centrosome do not contain their own DNA-basedgenomes. While it was confirmed that RNA molecules associate with centrosomes, the sequences have still beenfound within the nucleus. Furthermore, centrosomes can form de novo after having been removed (e.g. by laserirradiation) from normal cells.

References

DNA 101

DNA

The structure of the DNA double helix. The atoms in the structure are colour-coded byelement and the detailed structure of two base pairs are shown in the bottom right.

The structure of part of a DNA double helix

Deoxyribonucleic acid (DNA) is amolecule that encodes the geneticinstructions used in the developmentand functioning of all known livingorganisms and many viruses. DNA is anucleic acid; alongside proteins andcarbohydrates, nucleic acids composethe three major macromoleculesessential for all known forms of life.Most DNA molecules aredouble-stranded helices, consisting oftwo long biopolymers made of simplerunits called nucleotides—eachnucleotide is composed of anucleobase (guanine, adenine,thymine, and cytosine), recorded usingthe letters G, A, T, and C, as well as abackbone made of alternating sugars(deoxyribose) and phosphate groups(related to phosphoric acid), with thenucleobases (G, A, T, C) attached tothe sugars.

DNA is well-suited for biologicalinformation storage. The DNAbackbone is resistant to cleavage, andboth strands of the double-strandedstructure store the same biologicalinformation. Biological information isreplicated as the two strands areseparated.The two strands of DNA run inopposite directions to each other andare therefore anti-parallel, onebackbone being 3′ (three prime) andthe other 5′ (five prime). This refers tothe direction the 3rd and 5th carbon onthe sugar molecule is facing. Attachedto each sugar is one of four types ofmolecules called nucleobases(informally, bases). It is the sequenceof these four nucleobases along thebackbone that encodes biological

DNA 102

information. Under the genetic code, RNA strands are translated to specify the sequence of amino acids withinproteins. These RNA strands are initially created using DNA strands as a template in a process called transcription.Within cells, DNA is organized into long structures called chromosomes. During cell division these chromosomesare duplicated in the process of DNA replication, providing each cell its own complete set of chromosomes.Eukaryotic organisms (animals, plants, fungi, and protists) store most of their DNA inside the cell nucleus and someof their DNA in organelles, such as mitochondria or chloroplasts. In contrast, prokaryotes (bacteria and archaea)store their DNA only in the cytoplasm. Within the chromosomes, chromatin proteins such as histones compact andorganize DNA. These compact structures guide the interactions between DNA and other proteins, helping controlwhich parts of the DNA are transcribed.Scientists use DNA as a molecular tool to explore physical laws and theories, such as the ergodic theorem and thetheory of elasticity. The unique material properties of DNA have made it an attractive molecule for materialscientists and engineers interested in micro- and nano-fabrication. Among notable advances in this field are DNAorigami and DNA-based hybrid materials.The obsolete synonym "desoxyribonucleic acid" may occasionally be encountered, for example, in pre-1953genetics.

Properties

Chemical structure of DNA. Hydrogen bonds shown as dotted lines.

DNA is a long polymer made fromrepeating units called nucleotides.[1] DNAwas first identified and isolated by FriedrichMiescher and the double helix structure ofDNA was first discovered by James Watsonand Francis Crick. The structure of DNA ofall species comprises two helical chainseach coiled round the same axis, and eachwith a pitch of 34 ångströms(3.4 nanometres) and a radius of10 ångströms (1.0 nanometres). Accordingto another study, when measured in aparticular solution, the DNA chain measured22 to 26 ångströms wide (2.2 to2.6 nanometres), and one nucleotide unitmeasured 3.3 Å (0.33 nm) long. Althougheach individual repeating unit is very small,DNA polymers can be very large moleculescontaining millions of nucleotides. Forinstance, the largest human chromosome,chromosome number 1, consists ofapproximately 220 million base pairs and is85 mm long.

In living organisms DNA does not usually exist as a single molecule, but instead as a pair of molecules that are heldtightly together.[2] These two long strands entwine like vines, in the shape of a double helix. The nucleotide repeatscontain both the segment of the backbone of the molecule, which holds the chain together, and a nucleobase, which

interacts with the other DNA strand in the helix. A nucleobase linked to a sugar is called a nucleoside and a base linked to a sugar and one or more phosphate groups is called a nucleotide. A polymer comprising multiple linked

DNA 103

nucleotides (as in DNA) is called a polynucleotide.[3]

The backbone of the DNA strand is made from alternating phosphate and sugar residues. The sugar in DNA is2-deoxyribose, which is a pentose (five-carbon) sugar. The sugars are joined together by phosphate groups that formphosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These asymmetric bondsmean a strand of DNA has a direction. In a double helix the direction of the nucleotides in one strand is opposite totheir direction in the other strand: the strands are antiparallel. The asymmetric ends of DNA strands are called the 5′(five prime) and 3′ (three prime) ends, with the 5′ end having a terminal phosphate group and the 3′ end a terminalhydroxyl group. One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA beingreplaced by the alternative pentose sugar ribose in RNA.

A section of DNA. The bases liehorizontally between the two

spiraling strands.[4] (animatedversion).

The DNA double helix is stabilized primarily by two forces: hydrogen bondsbetween nucleotides and base-stacking interactions among aromatic nucleobases.In the aqueous environment of the cell, the conjugated π bonds of nucleotidebases align perpendicular to the axis of the DNA molecule, minimizing theirinteraction with the solvation shell and therefore, the Gibbs free energy. The fourbases found in DNA are adenine (abbreviated A), cytosine (C), guanine (G) andthymine (T). These four bases are attached to the sugar/phosphate to form thecomplete nucleotide, as shown for adenosine monophosphate.

Nucleobase classification

The nucleobases are classified into two types: the purines, A and G, being fusedfive- and six-membered heterocyclic compounds, and the pyrimidines, thesix-membered rings C and T. A fifth pyrimidine nucleobase, uracil (U), usuallytakes the place of thymine in RNA and differs from thymine by lacking a methylgroup on its ring. In addition to RNA and DNA a large number of artificialnucleic acid analogues have also been created to study the properties of nucleicacids, or for use in biotechnology.

Uracil is not usually found in DNA, occurring only as a breakdown product ofcytosine. However in a number of bacteriophages – Bacillus subtilisbacteriophages PBS1 and PBS2 and Yersinia bacteriophage piR1-37 – thymine has been replaced by uracil.

Base J (beta-d-glucopyranosyloxymethyluracil), a modified form of uracil, is also found in a number of organisms:the flagellates Diplonema and Euglena, and all the kinetoplastid genera Biosynthesis of J occurs in two steps: in thefirst step a specific thymidine in DNA is converted into hydroxymethyldeoxyuridine; in the second HOMedU isglycosylated to form J. Proteins that bind specifically to this base have been identified. These proteins appear to bedistant relatives of the Tet1 oncogene that is involved in the pathogenesis of acute myeloid leukemia. J appears to actas a termination signal for RNA polymerase II.

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Major and minor grooves of DNA. Minor grooveis a binding site for the dye Hoechst 33258.

Grooves

Twin helical strands form the DNA backbone. Another double helixmay be found tracing the spaces, or grooves, between the strands.These voids are adjacent to the base pairs and may provide a bindingsite. As the strands are not symmetrically located with respect to eachother, the grooves are unequally sized. One groove, the major groove,is 22 Å wide and the other, the minor groove, is 12 Å wide. Thenarrowness of the minor groove means that the edges of the bases aremore accessible in the major groove. As a result, proteins liketranscription factors that can bind to specific sequences in

double-stranded DNA usually make contacts to the sides of the bases exposed in the major groove. This situationvaries in unusual conformations of DNA within the cell (see below), but the major and minor grooves are alwaysnamed to reflect the differences in size that would be seen if the DNA is twisted back into the ordinary B form.

Base pairingIn a DNA double helix, each type of nucleobase on one strand bonds with just one type of nucleobase on the otherstrand. This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with adeninebonding only to thymine in two hydrogen bonds, and cytosine bonding only to guanine in three hydrogen bonds.This arrangement of two nucleotides binding together across the double helix is called a base pair. As hydrogenbonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helixcan therefore be pulled apart like a zipper, either by a mechanical force or high temperature. As a result of thiscomplementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand,which is vital in DNA replication. Indeed, this reversible and specific interaction between complementary base pairsis critical for all the functions of DNA in living organisms.

Top, a GC base pair with three hydrogen bonds. Bottom, an AT base pair with two hydrogen bonds. Non-covalenthydrogen bonds between the pairs are shown as dashed lines.The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GCforming three hydrogen bonds (see figures, right). DNA with high GC-content is more stable than DNA with lowGC-content.As noted above, most DNA molecules are actually two polymer strands, bound together in a helical fashion bynoncovalent bonds; this double stranded structure (dsDNA) is maintained largely by the intrastrand base stackinginteractions, which are strongest for G,C stacks. The two strands can come apart – a process known as melting – toform two single-stranded DNA molecules (ssDNA) molecules. Melting occurs at high temperature, low salt and highpH (low pH also melts DNA, but since DNA is unstable due to acid depurination, low pH is rarely used).

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The stability of the dsDNA form depends not only on the GC-content (% G,C basepairs) but also on sequence (sincestacking is sequence specific) and also length (longer molecules are more stable). The stability can be measured invarious ways; a common way is the "melting temperature", which is the temperature at which 50% of the dsmolecules are converted to ss molecules; melting temperature is dependent on ionic strength and the concentration ofDNA. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix thatdetermines the strength of the association between the two strands of DNA. Long DNA helices with a highGC-content have stronger-interacting strands, while short helices with high AT content have weaker-interactingstrands. In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box insome promoters, tend to have a high AT content, making the strands easier to pull apart.In the laboratory, the strength of this interaction can be measured by finding the temperature necessary to break thehydrogen bonds, their melting temperature (also called Tm value). When all the base pairs in a DNA double helixmelt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNAmolecules (ssDNA) have no single common shape, but some conformations are more stable than others.

Sense and antisenseA DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA copy that is translated intoprotein.[5] The sequence on the opposite strand is called the "antisense" sequence. Both sense and antisensesequences can exist on different parts of the same strand of DNA (i.e. both strands can contain both sense andantisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functionsof these RNAs are not entirely clear. One proposal is that antisense RNAs are involved in regulating gene expressionthrough RNA-RNA base pairing.A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction betweensense and antisense strands by having overlapping genes. In these cases, some DNA sequences do double duty,encoding one protein when read along one strand, and a second protein when read in the opposite direction along theother strand. In bacteria, this overlap may be involved in the regulation of gene transcription, while in viruses,overlapping genes increase the amount of information that can be encoded within the small viral genome.

SupercoilingDNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strandusually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands becomemore tightly or more loosely wound. If the DNA is twisted in the direction of the helix, this is positive supercoiling,and the bases are held more tightly together. If they are twisted in the opposite direction, this is negativesupercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that isintroduced by enzymes called topoisomerases. These enzymes are also needed to relieve the twisting stressesintroduced into DNA strands during processes such as transcription and DNA replication.

From left to right, the structures of A, B and ZDNA

Alternate DNA structures

DNA exists in many possible conformations that include A-DNA,B-DNA, and Z-DNA forms, although, only B-DNA and Z-DNA havebeen directly observed in functional organisms. The conformation thatDNA adopts depends on the hydration level, DNA sequence, theamount and direction of supercoiling, chemical modifications of thebases, the type and concentration of metal ions, as well as the presenceof polyamines in solution.

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The first published reports of A-DNA X-ray diffraction patterns—and also B-DNA—used analyses based onPatterson transforms that provided only a limited amount of structural information for oriented fibers of DNA. Analternate analysis was then proposed by Wilkins et al., in 1953, for the in vivo B-DNA X-ray diffraction/scatteringpatterns of highly hydrated DNA fibers in terms of squares of Bessel functions. In the same journal, James Watsonand Francis Crick presented their molecular modeling analysis of the DNA X-ray diffraction patterns to suggest thatthe structure was a double-helix.Although the "B-DNA form" is most common under the conditions found in cells, it is not a well-definedconformation but a family of related DNA conformations[6] that occur at the high hydration levels present in livingcells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with asignificant degree of disorder.[7]

Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and anarrower, deeper major groove. The A form occurs under non-physiological conditions in partially dehydratedsamples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, as well as inenzyme-DNA complexes. Segments of DNA where the bases have been chemically modified by methylation mayundergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in aleft-handed spiral, the opposite of the more common B form. These unusual structures can be recognized by specificZ-DNA binding proteins and may be involved in the regulation of transcription.

Alternate DNA chemistryFor a number of years exobiologists have proposed the existence of a shadow biosphere, a postulated microbialbiosphere of Earth that uses radically different biochemical and molecular processes than currently known life. Oneof the proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA. A report in 2010 ofthe possibility in the bacterium GFAJ-1, was announced, though the research was disputed, and evidence suggeststhe bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules.

Quadruplex structuresAt the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of theseregions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normallyreplicate DNA cannot copy the extreme 3′ ends of chromosomes. These specialized chromosome caps also helpprotect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected. Inhuman cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simpleTTAGGG sequence.

DNA quadruplex formed by telomere repeats.The looped conformation of the DNA backboneis very different from the typical DNA helix.[8]

These guanine-rich sequences may stabilize chromosome ends byforming structures of stacked sets of four-base units, rather than theusual base pairs found in other DNA molecules. Here, four guaninebases form a flat plate and these flat four-base units then stack on topof each other, to form a stable G-quadruplex structure. These structuresare stabilized by hydrogen bonding between the edges of the bases andchelation of a metal ion in the centre of each four-base unit. Otherstructures can also be formed, with the central set of four bases comingfrom either a single strand folded around the bases, or several differentparallel strands, each contributing one base to the central structure.

In addition to these stacked structures, telomeres also form large loopstructures called telomere loops, or T-loops. Here, the single-stranded

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DNA curls around in a long circle stabilized by telomere-binding proteins. At the very end of the T-loop, thesingle-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting thedouble-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacementloop or D-loop.

Single branch Multiple branches

Branched DNA can form networks containing multiple branches.

Branched DNAIn DNA fraying occurs when non-complementary regions exist at the end of an otherwise complementarydouble-strand of DNA. However, branched DNA can occur if a third strand of DNA is introduced and containsadjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplestexample of branched DNA involves only three strands of DNA, complexes involving additional strands and multiplebranches are also possible. Branched DNA can be used in nanotechnology to construct geometric shapes, see thesection on uses in technology below.

Chemical modifications and altered DNA packaging

cytosine 5-methylcytosine thymine

Structure of cytosine with and without the 5-methyl group. Deamination converts 5-methylcytosine into thymine.

Base modifications and DNA packagingThe expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin.Base modifications can be involved in packaging, with regions that have low or no gene expression usuallycontaining high levels of methylation of cytosine bases. DNA packaging and its influence on gene expression canalso occur by covalent modifications of the histone protein core around which DNA is wrapped in the chromatinstructure or else by remodeling carried out by chromatin remodeling complexes (see Chromatin remodeling). Thereis, further, crosstalk between DNA methylation and histone modification, so they can coordinately affect chromatinand gene expression.[9]

For one example, cytosine methylation, produces 5-methylcytosine, which is important for X-chromosomeinactivation. The average level of methylation varies between organisms – the worm Caenorhabditis elegans lackscytosine methylation, while vertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine.Despite the importance of 5-methylcytosine, it can deaminate to leave a thymine base, so methylated cytosines areparticularly prone to mutations. Other base modifications include adenine methylation in bacteria, the presence of5-hydroxymethylcytosine in the brain, and the glycosylation of uracil to produce the "J-base" in kinetoplastids.

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Damage

A covalent adduct between a metabolicallyactivated form of benzo[a]pyrene, the majormutagen in tobacco smoke, and DNA[10]

DNA can be damaged by many sorts of mutagens, which change theDNA sequence. Mutagens include oxidizing agents, alkylating agentsand also high-energy electromagnetic radiation such as ultraviolet lightand X-rays. The type of DNA damage produced depends on the type ofmutagen. For example, UV light can damage DNA by producingthymine dimers, which are cross-links between pyrimidine bases. Onthe other hand, oxidants such as free radicals or hydrogen peroxideproduce multiple forms of damage, including base modifications,particularly of guanosine, and double-strand breaks. A typical humancell contains about 150,000 bases that have suffered oxidative damage.Of these oxidative lesions, the most dangerous are double-strandbreaks, as these are difficult to repair and can produce point mutations,insertions and deletions from the DNA sequence, as well aschromosomal translocations. These mutations can cause cancer.Because of inherent limitations in the DNA repair mechanisms, ifhumans lived long enough, they would all eventually develop cancer.DNA damages that are naturally occurring, due to normal cellularprocesses that produce reactive oxygen species, the hydrolyticactivities of cellular water, etc., also occur frequently. Although mostof these damages are repaired, in any cell some DNA damage may remain despite the action of repair processes.These remaining DNA damages accumulate with age in mammalian postmitotic tissues. This accumulation appearsto be an important underlying cause of aging.[11]

Many mutagens fit into the space between two adjacent base pairs, this is called intercalation. Most intercalators arearomatic and planar molecules; examples include ethidium bromide, acridines, daunomycin, and doxorubicin. For anintercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of thedouble helix. This inhibits both transcription and DNA replication, causing toxicity and mutations. As a result, DNAintercalators may be carcinogens, and in the case of thalidomide, a teratogen. Others such as benzo[a]pyrene diolepoxide and aflatoxin form DNA adducts that induce errors in replication. Nevertheless, due to their ability to inhibitDNA transcription and replication, other similar toxins are also used in chemotherapy to inhibit rapidly growingcancer cells.

Biological functionsDNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set ofchromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNAarranged into 46 chromosomes. The information carried by DNA is held in the sequence of pieces of DNA calledgenes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, intranscription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNAsequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is thenused to make a matching protein sequence in a process called translation, which depends on the same interactionbetween RNA nucleotides. In alternative fashion, a cell may simply copy its genetic information in a process calledDNA replication. The details of these functions are covered in other articles; here we focus on the interactionsbetween DNA and other molecules that mediate the function of the genome.

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Genes and genomesGenomic DNA is tightly and orderly packed in the process called DNA condensation to fit the small availablevolumes of the cell. In eukaryotes, DNA is located in the cell nucleus, as well as small amounts in mitochondria andchloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid.The genetic information in a genome is held within genes, and the complete set of this information in an organism iscalled its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic inan organism. Genes contain an open reading frame that can be transcribed, as well as regulatory sequences such aspromoters and enhancers, which control the transcription of the open reading frame.In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting ofnon-coding repetitive sequences. The reasons for the presence of so much noncoding DNA in eukaryotic genomesand the extraordinary differences in genome size, or C-value, among species represent a long-standing puzzle knownas the "C-value enigma". However, some DNA sequences that do not code protein may still encode functionalnon-coding RNA molecules, which are involved in the regulation of gene expression.

T7 RNA polymerase (blue) producing a mRNA(green) from a DNA template (orange).[12]

Some noncoding DNA sequences play structural roles inchromosomes. Telomeres and centromeres typically contain few genes,but are important for the function and stability of chromosomes. Anabundant form of noncoding DNA in humans are pseudogenes, whichare copies of genes that have been disabled by mutation. Thesesequences are usually just molecular fossils, although they canoccasionally serve as raw genetic material for the creation of newgenes through the process of gene duplication and divergence.

Transcription and translation

A gene is a sequence of DNA that contains genetic information andcan influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines amessenger RNA sequence, which then defines one or more protein sequences. The relationship between thenucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation,known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from asequence of three nucleotides (e.g. ACT, CAG, TTT).

In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is thendecoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, whichcarries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons ( combinations). These encode the twenty standard amino acids, giving most amino acids more than one possiblecodon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA,TGA and TAG codons.

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DNA replication. The double helix is unwound by a helicase and topoisomerase. Next,one DNA polymerase produces the leading strand copy. Another DNA polymerase binds

to the lagging strand. This enzyme makes discontinuous segments (called Okazakifragments) before DNA ligase joins them together.

Replication

Cell division is essential for anorganism to grow, but, when a celldivides, it must replicate the DNA inits genome so that the two daughtercells have the same geneticinformation as their parent. Thedouble-stranded structure of DNAprovides a simple mechanism for DNAreplication. Here, the two strands areseparated and then each strand'scomplementary DNA sequence isrecreated by an enzyme called DNApolymerase. This enzyme makes thecomplementary strand by finding the correct base through complementary base pairing, and bonding it onto theoriginal strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms areused to copy the antiparallel strands of the double helix. In this way, the base on the old strand dictates which baseappears on the new strand, and the cell ends up with a perfect copy of its DNA.

Interactions with proteins

All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or theprotein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, thepolymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.

DNA-binding proteins

Interaction of DNA (shown in orange) with histones (shown in blue). These proteins' basic amino acids bind to theacidic phosphate groups on DNA.Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin. In eukaryotes this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved. The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are therefore largely independent of the base sequence. Chemical modifications of these basic amino acid residues include methylation, phosphorylation and acetylation. These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription. Other non-specific DNA-binding

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proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted DNA. These proteinsare important in bending arrays of nucleosomes and arranging them into the larger structures that make upchromosomes.A distinct group of DNA-binding proteins are the DNA-binding proteins that specifically bind single-stranded DNA.In humans, replication protein A is the best-understood member of this family and is used in processes where thedouble helix is separated, including DNA replication, recombination and DNA repair. These binding proteins seemto stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.

The lambda repressorhelix-turn-helix transcription factor

bound to its DNA target[13]

In contrast, other proteins have evolved to bind to particular DNA sequences.The most intensively studied of these are the various transcription factors, whichare proteins that regulate transcription. Each transcription factor binds to oneparticular set of DNA sequences and activates or inhibits the transcription ofgenes that have these sequences close to their promoters. The transcriptionfactors do this in two ways. Firstly, they can bind the RNA polymeraseresponsible for transcription, either directly or through other mediator proteins;this locates the polymerase at the promoter and allows it to begin transcription.Alternatively, transcription factors can bind enzymes that modify the histones atthe promoter. This changes the accessibility of the DNA template to thepolymerase.

As these DNA targets can occur throughout an organism's genome, changes inthe activity of one type of transcription factor can affect thousands of genes.Consequently, these proteins are often the targets of the signal transductionprocesses that control responses to environmental changes or cellulardifferentiation and development. The specificity of these transcription factors'interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowingthem to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases aremost accessible.

The restriction enzyme EcoRV (green) in acomplex with its substrate DNA[14]

DNA-modifying enzymes

Nucleases and ligases

Nucleases are enzymes that cut DNA strands by catalyzing thehydrolysis of the phosphodiester bonds. Nucleases that hydrolysenucleotides from the ends of DNA strands are called exonucleases,while endonucleases cut within strands. The most frequently usednucleases in molecular biology are the restriction endonucleases, whichcut DNA at specific sequences. For instance, the EcoRV enzymeshown to the left recognizes the 6-base sequence 5′-GATATC-3′ and

makes a cut at the vertical line. In nature, these enzymes protect bacteria against phage infection by digesting thephage DNA when it enters the bacterial cell, acting as part of the restriction modification system. In technology,these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.

Enzymes called DNA ligases can rejoin cut or broken DNA strands. Ligases are particularly important in laggingstrand DNA replication, as they join together the short segments of DNA produced at the replication fork into acomplete copy of the DNA template. They are also used in DNA repair and genetic recombination.

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Topoisomerases and helicases

Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount ofsupercoiling in DNA. Some of these enzymes work by cutting the DNA helix and allowing one section to rotate,thereby reducing its level of supercoiling; the enzyme then seals the DNA break. Other types of these enzymes arecapable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining thehelix. Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates,predominantly ATP, to break hydrogen bonds between bases and unwind the DNA double helix into single strands.These enzymes are essential for most processes where enzymes need to access the DNA bases.

Polymerases

Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of theirproducts are created based on existing polynucleotide chains—which are called templates. These enzymes functionby repeatedly adding a nucleotide to the 3′ hydroxyl group at the end of the growing polynucleotide chain. As aconsequence, all polymerases work in a 5′ to 3′ direction. In the active site of these enzymes, the incomingnucleoside triphosphate base-pairs to the template: this allows polymerases to accurately synthesize thecomplementary strand of their template. Polymerases are classified according to the type of template that they use.In DNA replication, DNA-dependent DNA polymerases make copies of DNA polynucleotide chains. In order topreserve biological information, it is essential that the sequence of bases in each copy are precisely complementaryto the sequence of bases in the template strand. Many DNA polymerases have a proofreading activity. Here, thepolymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between themismatched nucleotides. If a mismatch is detected, a 3′ to 5′ exonuclease activity is activated and the incorrect baseremoved. In most organisms, DNA polymerases function in a large complex called the replisome that containsmultiple accessory subunits, such as the DNA clamp or helicases.RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strandinto DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells byretroviruses, and telomerase, which is required for the replication of telomeres. Telomerase is an unusual polymerasebecause it contains its own RNA template as part of its structure.Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand intoRNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter andseparates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches aregion of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependentDNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome,operates as part of a large protein complex with multiple regulatory and accessory subunits.

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Genetic recombination

Structure of the Holliday junction intermediate in genetic recombination. The four separate DNA strands arecoloured red, blue, green and yellow.[15]

Recombination involves the breakage and rejoining of twochromosomes (M and F) to produce two re-arranged chromosomes

(C1 and C2).

A DNA helix usually does not interact with othersegments of DNA, and in human cells the differentchromosomes even occupy separate areas in thenucleus called "chromosome territories". This physicalseparation of different chromosomes is important forthe ability of DNA to function as a stable repository forinformation, as one of the few times chromosomesinteract is during chromosomal crossover when theyrecombine. Chromosomal crossover is when two DNAhelices break, swap a section and then rejoin.

Recombination allows chromosomes to exchangegenetic information and produces new combinations ofgenes, which increases the efficiency of naturalselection and can be important in the rapid evolution of

new proteins. Genetic recombination can also be involved in DNA repair, particularly in the cell's response todouble-strand breaks.

The most common form of chromosomal crossover is homologous recombination, where the two chromosomesinvolved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can producechromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes knownas recombinases, such as RAD51. The first step in recombination is a double-stranded break caused by either anendonuclease or damage to the DNA. A series of steps catalyzed in part by the recombinase then leads to joining ofthe two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed tothe complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can bemoved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then haltedby cleavage of the junction and re-ligation of the released DNA.

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EvolutionDNA contains the genetic information that allows all modern living things to function, grow and reproduce.However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has beenproposed that the earliest forms of life may have used RNA as their genetic material. RNA may have acted as thecentral part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part ofribozymes. This ancient RNA world where nucleic acid would have been used for both catalysis and genetics mayhave influenced the evolution of the current genetic code based on four nucleotide bases. This would occur, since thenumber of different bases in such an organism is a trade-off between a small number of bases increasing replicationaccuracy and a large number of bases increasing the catalytic efficiency of ribozymes.However, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible.This is because DNA survives in the environment for less than one million years, and slowly degrades into shortfragments in solution. Claims for older DNA have been made, most notably a report of the isolation of a viablebacterium from a salt crystal 250 million years old, but these claims are controversial.On 8 August 2011, a report, based on NASA studies with meteorites found on Earth, was published suggestingbuilding blocks of DNA (adenine, guanine and related organic molecules) may have been formed extraterrestrially inouter space.

Uses in technology

Genetic engineeringMethods have been developed to purify DNA from organisms, such as phenol-chloroform extraction, and tomanipulate it in the laboratory, such as restriction digests and the polymerase chain reaction. Modern biology andbiochemistry make intensive use of these techniques in recombinant DNA technology. Recombinant DNA is aman-made DNA sequence that has been assembled from other DNA sequences. They can be transformed intoorganisms in the form of plasmids or in the appropriate format, by using a viral vector. The genetically modifiedorganisms produced can be used to produce products such as recombinant proteins, used in medical research, or begrown in agriculture.

ForensicsForensic scientists can use DNA in blood, semen, skin, saliva or hair found at a crime scene to identify a matchingDNA of an individual, such as a perpetrator. This process is formally termed DNA profiling, but may also be called"genetic fingerprinting". In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandemrepeats and minisatellites, are compared between people. This method is usually an extremely reliable technique foridentifying a matching DNA. However, identification can be complicated if the scene is contaminated with DNAfrom several people. DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys, and first used inforensic science to convict Colin Pitchfork in the 1988 Enderby murders case.[16]

The development of forensic science, and the ability to now obtain genetic matching on minute samples of blood,skin, saliva or hair has led to a re-examination of a number of cases. Evidence can now be uncovered that was notscientifically possible at the time of the original examination. Combined with the removal of the double jeopardy lawin some places, this can allow cases to be reopened where previous trials have failed to produce sufficient evidenceto convince a jury. People charged with serious crimes may be required to provide a sample of DNA for matchingpurposes. The most obvious defence to DNA matches obtained forensically is to claim that cross-contamination ofevidence has taken place. This has resulted in meticulous strict handling procedures with new cases of serious crime.DNA profiling is also used to identify victims of mass casualty incidents. As well as positively identifying bodies orbody parts in serious accidents, DNA profiling is being successfully used to identify individual victims in mass wargraves – matching to family members.

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BioinformaticsBioinformatics involves the manipulation, searching, and data mining of biological data, and this includes DNAsequence data. The development of techniques to store and search DNA sequences have led to widely appliedadvances in computer science, especially string searching algorithms, machine learning and database theory. Stringsearching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence ofletters, were developed to search for specific sequences of nucleotides.[17] The DNA sequence may be aligned withother DNA sequences to identify homologous sequences and locate the specific mutations that make them distinct.These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships andprotein function. Data sets representing entire genomes' worth of DNA sequences, such as those produced by theHuman Genome Project, are difficult to use without the annotations that identify the locations of genes andregulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associatedwith protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predictthe presence of particular gene products and their possible functions in an organism even before they have beenisolated experimentally. Entire genomes may also be compared, which can shed light on the evolutionary history ofparticular organism and permit the examination of complex evolutionary events.

DNA nanotechnology

The DNA structure at left (schematic shown) will self-assemble into the structurevisualized by atomic force microscopy at right. DNA nanotechnology is the field that

seeks to design nanoscale structures using the molecular recognition properties of DNAmolecules. Image from Strong, 2004 [18].

DNA nanotechnology uses the uniquemolecular recognition properties ofDNA and other nucleic acids to createself-assembling branched DNAcomplexes with useful properties.DNA is thus used as a structuralmaterial rather than as a carrier ofbiological information. This has led tothe creation of two-dimensionalperiodic lattices (both tile-based aswell as using the "DNA origami"method) as well as three-dimensionalstructures in the shapes of polyhedra.Nanomechanical devices andalgorithmic self-assembly have alsobeen demonstrated, and these DNAstructures have been used to template the arrangement of other molecules such as gold nanoparticles and streptavidinproteins.

History and anthropology

Because DNA collects mutations over time, which are then inherited, it contains historical information, and, bycomparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny. This fieldof phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared,population geneticists can learn the history of particular populations. This can be used in studies ranging fromecological genetics to anthropology; For example, DNA evidence is being used to try to identify the Ten Lost Tribesof Israel.[19][20]

DNA has also been used to look at modern family relationships, such as establishing family relationships between the descendants of Sally Hemings and Thomas Jefferson. This usage is closely related to the use of DNA in criminal

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investigations detailed above. Indeed, some criminal investigations have been solved when DNA from crime sceneshas matched relatives of the guilty individual.[21]

Information storageIn a paper published in Nature in January, 2013, scientists from the European Bioinformatics Institute and AgilentTechnologies proposed a mechanism to use DNA's ability to code information as a means of digital data storage. Thegroup was able to encode 739 kilobytes of data into DNA code, synthesize the actual DNA, then sequence the DNAand decode the information back to its original form, with a reported 100% accuracy. The encoded informationconsisted of text files and audio files. A prior experiment was published in August 2012. It was conducted byresearchers at Harvard University, where the text of a 54,000-word book was encoded in DNA.

History of DNA research

James Watson and Francis Crick (right),co-originators of the double-helix model, with

Maclyn McCarty (left).

DNA was first isolated by the Swiss physician Friedrich Miescherwho, in 1869, discovered a microscopic substance in the pus ofdiscarded surgical bandages. As it resided in the nuclei of cells, hecalled it "nuclein". In 1878, Albrecht Kossel isolated the non-proteincomponent of "nuclein", nucleic acid, and later isolated its five primarynucleobases. In 1919, Phoebus Levene identified the base, sugar andphosphate nucleotide unit. Levene suggested that DNA consisted of astring of nucleotide units linked together through the phosphate groups.However, Levene thought the chain was short and the bases repeated ina fixed order. In 1937 William Astbury produced the first X-raydiffraction patterns that showed that DNA had a regular structure.

In 1927, Nikolai Koltsov proposed that inherited traits would beinherited via a "giant hereditary molecule" made up of "two mirror strands that would replicate in asemi-conservative fashion using each strand as a template". In 1928, Frederick Griffith in his experiment discoveredthat traits of the "smooth" form of Pneumococcus could be transferred to the "rough" form of the same bacteria bymixing killed "smooth" bacteria with the live "rough" form. This system provided the first clear suggestion that DNAcarries genetic information—the Avery–MacLeod–McCarty experiment—when Oswald Avery, along withcoworkers Colin MacLeod and Maclyn McCarty, identified DNA as the transforming principle in 1943. DNA's rolein heredity was confirmed in 1952, when Alfred Hershey and Martha Chase in the Hershey–Chase experimentshowed that DNA is the genetic material of the T2 phage.

In 1953, James Watson and Francis Crick suggested what is now accepted as the first correct double-helix model ofDNA structure in the journal Nature. Their double-helix, molecular model of DNA was then based on a single X-raydiffraction image (labeled as "Photo 51")[22] taken by Rosalind Franklin and Raymond Gosling in May 1952, as wellas the information that the DNA bases are paired — also obtained through private communications from ErwinChargaff in the previous years. Chargaff's rules played a very important role in establishing double-helixconfigurations for B-DNA as well as A-DNA.Experimental evidence supporting the Watson and Crick model was published in a series of five articles in the same issue of Nature.[23] Of these, Franklin and Gosling's paper was the first publication of their own X-ray diffraction data and original analysis method that partially supported the Watson and Crick model; this issue also contained an article on DNA structure by Maurice Wilkins and two of his colleagues, whose analysis and in vivo B-DNA X-ray patterns also supported the presence in vivo of the double-helical DNA configurations as proposed by Crick and Watson for their double-helix molecular model of DNA in the previous two pages of Nature. In 1962, after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine.[24] Nobel

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Prizes were awarded only to living recipients at the time. A debate continues about who should receive credit for thediscovery.In an influential presentation in 1957, Crick laid out the central dogma of molecular biology, which foretold therelationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis".[25] Final confirmation ofthe replication mechanism that was implied by the double-helical structure followed in 1958 through theMeselson–Stahl experiment. Further work by Crick and coworkers showed that the genetic code was based onnon-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley and MarshallWarren Nirenberg to decipher the genetic code.[26] These findings represent the birth of molecular biology.

References[1] pp. 14–15.[2] Berg J., Tymoczko J. and Stryer L. (2002) Biochemistry. W. H. Freeman and Company ISBN 0-7167-4955-6[3] Abbreviations and Symbols for Nucleic Acids, Polynucleotides and their Constituents (http:/ / www. chem. qmul. ac. uk/ iupac/ misc/ naabb.

html) IUPAC-IUB Commission on Biochemical Nomenclature (CBN). Retrieved 3 January 2006.[4] Created from PDB 1D65 (http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1D65)[5] Designation of the two strands of DNA (http:/ / www. chem. qmul. ac. uk/ iubmb/ newsletter/ misc/ DNA. html) JCBN/NC-IUB Newsletter

1989. Retrieved 7 May 2008[6] http:/ / cogprints. org/ 3822/[7] Hosemann R., Bagchi R.N., Direct analysis of diffraction by matter, North-Holland Publs., Amsterdam – New York, 1962.[8] Created from NDB UD0017 (http:/ / ndbserver. rutgers. edu/ atlas/ xray/ structures/ U/ ud0017/ ud0017. html)[9][9] Hu Q, Rosenfeld MG. (2012) Epigenetic regulation of human embryonic stem cells. Front Genet. 3:238. doi: 10.3389/fgene.2012.00238.

PMID 23133442[10] Created from PDB 1JDG (http:/ / www. rcsb. org/ pdb/ cgi/ explore. cgi?pdbId=1JDG)[11] Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K (2008). Cancer and aging as consequences of un-repaired DNA damage. In:

New Research on DNA Damages (Editors: Honoka Kimura and Aoi Suzuki) Nova Science Publishers, Inc., New York, Chapter 1, pp. 1-47.open access, but read only https:/ / www. novapublishers. com/ catalog/ product_info. php?products_id=43247 ISBN 1604565810 ISBN978-1604565812

[12] Created from PDB 1MSW (http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1MSW)[13] Created from PDB 1LMB (http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1LMB)[14] Created from PDB 1RVA (http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1RVA)[15] Created from PDB 1M6G (http:/ / www. rcsb. org/ pdb/ explore/ explore. do?structureId=1M6G)[16] Colin Pitchfork — first murder conviction on DNA evidence also clears the prime suspect (http:/ / web. archive. org/ web/

20061214004903/ http:/ / www. forensic. gov. uk/ forensic_t/ inside/ news/ list_casefiles. php?case=1) Forensic Science Service Accessed 23December 2006

[17] Gusfield, Dan. Algorithms on Strings, Trees, and Sequences: Computer Science and Computational Biology. Cambridge University Press,15 January 1997. ISBN 978-0-521-58519-4.

[18] http:/ / dx. doi. org/ 10. 1371/ journal. pbio. 0020073[19] Lost Tribes of Israel, NOVA, PBS airdate: 22 February 2000. Transcript available from PBS.org (http:/ / www. pbs. org/ wgbh/ nova/

transcripts/ 2706israel. html). Retrieved 4 March 2006.[20] Kleiman, Yaakov. "The Cohanim/DNA Connection: The fascinating story of how DNA studies confirm an ancient biblical tradition". (http:/

/ www. aish. com/ societywork/ sciencenature/ the_cohanim_-_dna_connection. asp) aish.com (13 January 2000). Retrieved 4 March 2006.[21] Bhattacharya, Shaoni. "Killer convicted thanks to relative's DNA". (http:/ / www. newscientist. com/ article. ns?id=dn4908)

newscientist.com (20 April 2004). Retrieved 22 December 06.[22] The B-DNA X-ray pattern on the right of this linked image (http:/ / osulibrary. oregonstate. edu/ specialcollections/ coll/ pauling/ dna/

pictures/ sci9. 001. 5. html) was obtained by Rosalind Franklin and Raymond Gosling in May 1952 at high hydration levels of DNA and it hasbeen labeled as "Photo 51"

[23] Nature Archives Double Helix of DNA: 50 Years (http:/ / www. nature. com/ nature/ dna50/ archive. html)[24] The Nobel Prize in Physiology or Medicine 1962 (http:/ / nobelprize. org/ nobel_prizes/ medicine/ laureates/ 1962/ ) Nobelprize .org

Accessed 22 December 06[25] Crick, F.H.C. On degenerate templates and the adaptor hypothesis (PDF). (http:/ / genome. wellcome. ac. uk/ assets/ wtx030893. pdf)

genome.wellcome.ac.uk (Lecture, 1955). Retrieved 22 December 2006.[26] The Nobel Prize in Physiology or Medicine 1968 (http:/ / nobelprize. org/ nobel_prizes/ medicine/ laureates/ 1968/ ) Nobelprize.org

Accessed 22 December 06

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Further reading• Berry, Andrew; Watson, James. (2003). DNA: the secret of life. New York: Alfred A. Knopf.

ISBN 0-375-41546-7.• Calladine, Chris R.; Drew, Horace R.; Luisi, Ben F. and Travers, Andrew A. (2003). Understanding DNA: the

molecule & how it works. Amsterdam: Elsevier Academic Press. ISBN 0-12-155089-3.• Dennis, Carina; Julie Clayton (2003). 50 years of DNA. Basingstoke: Palgrave Macmillan. ISBN 1-4039-1479-6.• Judson, Horace F. 1979. The Eighth Day of Creation: Makers of the Revolution in Biology. Touchstone Books,

ISBN 0-671-22540-5. 2nd edition: Cold Spring Harbor Laboratory Press, 1996 paperback: ISBN 0-87969-478-5.• Olby, Robert C. (1994). The path to the double helix: the discovery of DNA. New York: Dover Publications.

ISBN 0-486-68117-3., first published in October 1974 by MacMillan, with foreword by Francis Crick;thedefinitive DNA textbook,revised in 1994 with a 9 page postscript

• Micklas, David. 2003. DNA Science: A First Course. Cold Spring Harbor Press: ISBN 978-0-87969-636-8• Ridley, Matt (2006). Francis Crick: discoverer of the genetic code. Ashland, OH: Eminent Lives, Atlas Books.

ISBN 0-06-082333-X.• Olby, Robert C. (2009). Francis Crick: A Biography. Plainview, N.Y: Cold Spring Harbor Laboratory Press.

ISBN 0-87969-798-9.• Rosenfeld, Israel. 2010. DNA: A Graphic Guide to the Molecule that Shook the World. Columbia University

Press: ISBN 978-0-231-14271-7• Schultz, Mark and Zander Cannon. 2009. The Stuff of Life: A Graphic Guide to Genetics and DNA. Hill and

Wang: ISBN 0-8090-8947-5• Stent, Gunther Siegmund; Watson, James. (1980). The double helix: a personal account of the discovery of the

structure of DNA. New York: Norton. ISBN 0-393-95075-1.• Watson, James. 2004. DNA: The Secret of Life. Random House: ISBN 978-0-09-945184-6• Wilkins, Maurice (2003). The third man of the double helix the autobiography of Maurice Wilkins. Cambridge,

Eng: University Press. ISBN 0-19-860665-6.

External links

Library resources

About DNA

• Online books (http:/ / tools. wmflabs. org/ ftl/ cgi-bin/ ftl?st=& su=DNA& library=OLBP)• Resources in your library (http:/ / tools. wmflabs. org/ ftl/ cgi-bin/ ftl?st=& su=DNA)• Resources in other libraries (http:/ / tools. wmflabs. org/ ftl/ cgi-bin/ ftl?st=& su=DNA& library=0CHOOSE0)

• DNA (http:/ / www. dmoz. org/ Science/ Biology/ Biochemistry_and_Molecular_Biology/ Biomolecules/Nucleic_Acids/ DNA/ / ) at the Open Directory Project

• DNA binding site prediction on protein (http:/ / pipe. scs. fsu. edu/ displar. html)• DNA the Double Helix Game (http:/ / nobelprize. org/ educational_games/ medicine/ dna_double_helix/ ) From

the official Nobel Prize web site• DNA under electron microscope (http:/ / www. fidelitysystems. com/ Unlinked_DNA. html)• Dolan DNA Learning Center (http:/ / www. dnalc. org/ )• Double Helix: 50 years of DNA (http:/ / www. nature. com/ nature/ dna50/ archive. html), Nature• Proteopedia DNA (http:/ / www. proteopedia. org/ wiki/ index. php/ DNA)• Proteopedia Forms_of_DNA (http:/ / www. proteopedia. org/ wiki/ index. php/ Forms_of_DNA)• ENCODE threads explorer (http:/ / www. nature. com/ encode/ ) ENCODE Home page. Nature (journal)• Double Helix 1953–2003 (http:/ / www. ncbe. reading. ac. uk/ DNA50/ ) National Centre for Biotechnology

Education

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• Genetic Education Modules for Teachers (http:/ / www. genome. gov/ 10506718)—DNA from the BeginningStudy Guide

• PDB Molecule of the Month pdb23_1 (http:/ / www. rcsb. org/ pdb/ static. do?p=education_discussion/molecule_of_the_month/ pdb23_1. html)

• Rosalind Franklin's contributions to the study of DNA (http:/ / mason. gmu. edu/ ~emoody/ rfranklin. html)• U.S. National DNA Day (http:/ / www. genome. gov/ 10506367)—watch videos and participate in real-time chat

with top scientists• Clue to chemistry of heredity found (http:/ / www. nytimes. com/ packages/ pdf/ science/ dna-article. pdf) The

New York Times June 1953. First American newspaper coverage of the discovery of the DNA structure• Olby R (2003). "Quiet debut for the double helix". Nature 421 (6921): 402–5. Bibcode: 2003Natur.421..402O

(http:/ / adsabs. harvard. edu/ abs/ 2003Natur. 421. . 402O). doi: 10.1038/nature01397 (http:/ / dx. doi. org/ 10.1038/ nature01397). PMID  12540907 (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 12540907).

• DNA from the Beginning (http:/ / www. dnaftb. org/ ) Another DNA Learning Center site on DNA, genes, andheredity from Mendel to the human genome project.

• The Register of Francis Crick Personal Papers 1938 – 2007 (http:/ / orpheus. ucsd. edu/ speccoll/ testing/ html/mss0660a. html#abstract) at Mandeville Special Collections Library, University of California, San Diego

• Seven-page, handwritten letter that Crick sent to his 12-year-old son Michael in 1953 describing the structure ofDNA. (http:/ / www. nature. com/ polopoly_fs/ 7. 9746!/ file/ Crick letter to Michael. pdf) See Crick’s medal goesunder the hammer (http:/ / www. nature. com/ news/ crick-s-medal-goes-under-the-hammer-1. 12705), Nature, 5April 2013.

Genome

Part of a series on

GeneticsKey components

•• Chromosome•• DNA•• RNA•• Genome•• Heredity•• Mutation•• Nucleotide•• Variation

• Glossary•• Index•• Outline

History and topics

•• Introduction•• History

• Evolution (molecular)•• Population genetics•• Mendelian inheritance•• Quantitative genetics•• Molecular genetics

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Research

•• DNA sequencing•• Genetic engineering

• Genomics ( template)•• Medical genetics

•• Branches of genetics

Biology portal

An image of the 46 chromosomes making up the diploid genome of ahuman male. (The mitochondrial chromosome is not shown.)

In modern molecular biology and genetics, the genomeis the entirety of an organism's hereditary information.It is encoded either in DNA or, for many types ofviruses, in RNA. The genome includes both the genesand the non-coding sequences of the DNA/RNA.[1]

Origin of term

The term was created in 1920 by Hans Winkler,professor of botany at the University of Hamburg,Germany. The Oxford English Dictionary suggests thename to be a blend of the words gene and chromosome.A few related -ome words already existed—such asbiome, rhizome and, more recently,connectome—forming a vocabulary into which genomefits systematically.

OverviewSome organisms have multiple copies of chromosomes: diploid, triploid, tetraploid and so on. In classical genetics,in a sexually reproducing organism (typically eukarya) the gamete has half the number of chromosomes of thesomatic cell and the genome is a full set of chromosomes in a gamete. In haploid organisms, including cells ofbacteria, archaea, and in organelles including mitochondria and chloroplasts, or viruses, that similarly contain genes,the single or set of circular and/or linear chains of DNA (or RNA for some viruses), likewise constitute the genome.The term genome can be applied specifically to mean what is stored on a complete set of nuclear DNA (i.e., the"nuclear genome") but can also be applied to what is stored within organelles that contain their own DNA, as withthe "mitochondrial genome" or the "chloroplast genome". Additionally, the genome can comprise non-chromosomalgenetic elements such as viruses, plasmids, and transposable elements.When people say that the genome of a sexually reproducing species has been "sequenced", typically they arereferring to a determination of the sequences of one set of autosomes and one of each type of sex chromosome,which together represent both of the possible sexes. Even in species that exist in only one sex, what is described as a"genome sequence" may be a composite read from the chromosomes of various individuals. Colloquially, the phrase"genetic makeup" is sometimes used to signify the genome of a particular individual or organism. The study of theglobal properties of genomes of related organisms is usually referred to as genomics, which distinguishes it fromgenetics which generally studies the properties of single genes or groups of genes.Both the number of base pairs and the number of genes vary widely from one species to another, and there is only arough correlation between the two (an observation known as the C-value paradox). At present, the highest knownnumber of genes is around 60,000, for the protozoan causing trichomoniasis (see List of sequenced eukaryoticgenomes), almost three times as many as in the human genome.

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An analogy to the human genome stored on DNA is that of instructions stored in a book:•• The book (genome) would contain 23 chapters (chromosomes);•• Each chapter contains 48 to 250 million letters (A,C,G,T) without spaces;•• Hence, the book contains over 3.2 billion letters total;•• The book fits into a cell nucleus the size of a pinpoint;• At least one copy of the book (all 23 chapters) is contained in most cells of our body. The only exception in

humans is found in mature red blood cells which become enucleated during development and therefore lack agenome.

Sequencing and mappingIn 1976, Walter Fiers at the University of Ghent (Belgium) was the first to establish the complete nucleotidesequence of a viral RNA-genome (bacteriophage MS2). The next year, Phage Φ-X174, with only 5386 base pairs,became the first DNA-genome project to be completed, by Fred Sanger. The first complete genome sequences forrepresentatives from all 3 domains of life were released within a short period during the mid-1990s. The firstbacterial genome to be sequenced was that of Haemophilus influenzae, completed by a team at The Institute forGenomic Research in 1995. A few months later, the first eukaryotic genome was completed, with the 16chromosomes of budding yeast Saccharomyces cerevisiae being released as the result of a European-led effort begunin the mid-1980s. Shortly afterward, in 1996, the first genome sequence for an archaeon, Methanococcus jannaschii,was completed, again by The Institute for Genomic Research.The development of new technologies has made it dramatically easier and cheaper to do sequencing, and the numberof complete genome sequences is growing rapidly. The US National Institutes of Health maintains one of severalcomprehensive databases of genomic information. Among the thousands of completed genome sequencing projectsinclude those for mouse, rice, the plant Arabidopsis thaliana, the puffer fish, and bacteria like E. coli.New sequencing technologies, such as massive parallel sequencing have also opened up the prospect of personalgenome sequencing as a diagnostic tool, as pioneered by Manteia Predictive Medicine. A major step toward that goalwas the completion in 2007 of the full genome of James D. Watson, one of the co-discoverers of the structure ofDNA.Whereas a genome sequence lists the order of every DNA base in a genome, a genome map identifies the landmarks.A genome map is less detailed than a genome sequence and aids in navigating around the genome. The HumanGenome Project was organized to map and to sequence the human genome. A fundamental step in the project wasthe release of a detailed genomic map by Jean Weissenbach and his team at the Genoscope in Paris.

Genome compositionsGenome composition is used to describe the make up of contents of a haploid genome, which should includegenome size, proportions of non-repetitive DNA and repetitive DNA in details. By comparing the genomecompositions between genomes, scientists can better understand the evolutionary history of a given genome.When talking about genome composition, one should distinguish between prokaryotes and eukaryotes as the bigdifferences on contents structure they have. In prokaryotes, most of the genome (85-90%) is non-repetitive DNA,which means coding DNA mainly forms it, while non-coding regions only take a small part. On the contrary,eukaryotes have the feature of exon-intron organization of protein coding genes; the variation of repetitive DNAcontent in eukaryotes is also extremely high. When refer to mammalians and plants, the major part of genome iscomposed by repetitive DNA.Most biological entities that are more complex than a virus sometimes or always carry additional genetic material besides that which resides in their chromosomes. In some contexts, such as sequencing the genome of a pathogenic microbe, "genome" is meant to include information stored on this auxiliary material, which is carried in plasmids. In

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such circumstances then, "genome" describes all of the genes and information on non-coding DNA that have thepotential to be present.In eukaryotes such as plants, protozoa and animals, however, "genome" carries the typical connotation of onlyinformation on chromosomal DNA. So although these organisms contain chloroplasts and/or mitochondria that havetheir own DNA, the genetic information contained by DNA within these organelles is not considered part of thegenome. In fact, mitochondria are sometimes said to have their own genome often referred to as the "mitochondrialgenome". The DNA found within the chloroplast may be referred to as the "plastome".

Genome size

Log-log plot of the total number of annotatedproteins in genomes submitted to GenBank as a

function of genome size.

Genome size is the total number of DNA base pairs in one copy of ahaploid genome. The genome size is positively correlated with themorphological complexity among prokaryotes and lower eukaryotes;however, after mollusks and all the other higher eukaryotes above, thiscorrelation is no longer effective. This phenomenon also indicates themighty influence coming from repetitive DNA act on the genomes.

Since genomes are very complex, one research strategy is to reduce thenumber of genes in a genome to the bare minimum and still have theorganism in question survive. There is experimental work being doneon minimal genomes for single cell organisms as well as minimalgenomes for multi-cellular organisms (see Developmental biology).The work is both in vivo and in silico.

Organismtype

Organism Genome size(base pairs)

Note

Virus Porcine circovirus type 1 1,759 1.8kb Smallest viruses replicating autonomously in eukaryotic cells.

Virus Bacteriophage MS2 3,569 3.5kb First sequenced RNA-genome

Virus SV40 5,224 5.2kb

Virus Phage Φ-X174 5,386 5.4kb First sequenced DNA-genome

Virus HIV 9,749 9.7kb

Virus Phage λ 48,502 48kb Often used as a vector for the cloning of recombinant DNA.

Virus Megavirus 1,259,197 1.3Mb Until 2013 the largest known viral genome.

Virus Pandoravirus salinus 2,470,000 2.47Mb Largest known viral genome.

Bacterium Haemophilus influenzae 1,830,000 1.8Mb First genome of a living organism sequenced, July 1995

Bacterium Carsonella ruddii 159,662 160kb Smallest non-viral genome.

Bacterium Buchnera aphidicola 600,000 600kb

Bacterium Wigglesworthia glossinidia 700,000 700Kb

Bacterium Escherichia coli 4,600,000 4.6Mb

Bacterium Solibacter usitatus (strain Ellin6076)

9,970,000 10Mb

Amoeboid Polychaos dubium ("Amoeba"dubia)

670,000,000,000 670Gb Largest known genome. (Disputed[2])

Plant Arabidopsis thaliana 157,000,000 157Mb First plant genome sequenced, December 2000.

Plant Genlisea margaretae 63,400,000 63Mb Smallest recorded flowering plant genome, 2006.

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Plant Fritillaria assyrica 130,000,000,000 130Gb

Plant Populus trichocarpa 480,000,000 480Mb First tree genome sequenced, September 2006

Plant Paris japonica (Japanese-native,pale-petal)

150,000,000,000 150Gb Largest plant genome known

Moss Physcomitrella patens 480,000,000 480Mb First genome of a bryophyte sequenced, January 2008.

Yeast Saccharomyces cerevisiae 12,100,000 12.1Mb First eukaryotic genome sequenced, 1996

Fungus Aspergillus nidulans 30,000,000 30Mb

Nematode Caenorhabditis elegans 100,300,000 100Mb First multicellular animal genome sequenced, December 1998

Nematode Pratylenchus coffeae 20,000,000 20Mb Smallest animal genome known

Insect Drosophila melanogaster (fruitfly)

130,000,000 130Mb

Insect Bombyx mori (silk moth) 432,000,000 432Mb 14,623 predicted genes

Insect Apis mellifera (honey bee) 236,000,000 236Mb

Insect Solenopsis invicta (fire ant) 480,000,000 480Mb

Fish Tetraodon nigroviridis (type ofpuffer fish)

385,000,000 390Mb Smallest vertebrate genome known estimated to be 340 Mb - 385Mb.

Mammal Mus musculus 2,700,000,000 2.7Gb

Mammal Homo sapiens 3,200,000,000 3.2Gb Homo sapiens estimated genome size 3.2 billion bp[3] Initialsequencing and analysis of the human genome

Fish Protopterus aethiopicus(marbled lungfish)

130,000,000,000 130Gb Largest vertebrate genome known

Proportion of non-repetitive DNAThe proportion of non-repetitive DNA is calculated by using length of non-repetitive DNA divided by genomesize. Protein-coding genes and RNA-coding genes are generally non-repetitive DNA. Bigger genome does not meanmore genes, and the proportion of non-repetitive DNA decreases along with the increase of genome size in highereukaryotes.It had been found that the proportion of non-repetitive DNA can vary a lot between species. Some E. coli asprokaryotes only have non-repetitive DNA, lower eukaryotes such as C. elegans and fruit fly, still possess morenon-repetitive DNA than repetitive DNA. Higher eukaryotes tend to have more repetitive DNA than non-repetitiveone. In some plants and amphibians, the proportion of non-repetitive DNA is no more than 20%, becoming aminority component.

Proportion of repetitive DNAThe proportion of repetitive DNA is calculated by using length of repetitive DNA divide by genome size. There aretwo categories of repetitive DNA in genome: tandem repeats and interspersed repeats.

Tandem repeats

Tandem repeats are usually caused by slippage during replication, unequal crossing-over and gene conversion,satellite DNA and microsatellites are forms of tandem repeats in the genome. Although tandem repeats count for asignificant proportion in genome, the largest proportion in mammalian is the other type, interspersed repeats.

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Interspersed repeats

Interspersed repeats mainly come from transposable elements (TEs), but they also include some protein codinggene families and pseudogenes. Transposable elements are able to integrate into the genome at another site withinthe cell. It is believed that TEs are an important driving force on genome evolution of higher eukaryotes. TEs can beclassified into two categories, Class 1 (retrotransposons) and Class 2 (DNA transposons).

Retrotransposons

Retrotransposons can be transcribed into RNA, which are then duplicated at another site into the genome.Retrotransposons can be divided into Long terminal repeats (LTRs) and Non-Long Terminal Repeats (Non-LTR).Long Terminal Repeats (LTRs)

similar to retroviruses, which have both gag and pol genes to make cDNA from RNA and proteins to insertinto genome, but LTRs can only act within the cell as they lack the env gene in retroviruses. It has beenreported that LTRs consist of the largest fraction in most plant genome and might account for the hugevariation in genome size.

Non-Long Terminal Repeats (Non-LTRs)can be divided into long interspersed elements (LINEs), short interspersed elements (SINEs) andPenelope-like elements. In Dictyostelium discoideum, there is another DIRS-like elements belong toNon-LTRs. Non-LTRs are widely spread in eukaryotic genomes.

Long interspersed elements (LINEs)are able to encode two Open Reading Frames (ORFs) to generate transcriptase and endonuclease, which areessential in retrotransposition. The human genome has around 500,000 LINEs, taking around 17% of thegenome.

Short interspersed elements (SINEs)are usually less than 500 base pairs and need to co-opt with the LINEs machinery to function asnonautonomous retrotransposons. The Alu element is the most common SINEs found in primates, it has alength of about 350 base pairs and takes about 11% of the human genome with around 1,500,000 copies.

DNA transposons

DNA transposons generally move by "cut and paste" in the genome, but duplication has also been observed. Class 2TEs do not use RNA as intermediate and are popular in bacteria, in metazoan it has also been found.

Genome evolutionGenomes are more than the sum of an organism's genes and have traits that may be measured and studied withoutreference to the details of any particular genes and their products. Researchers compare traits such as chromosomenumber (karyotype), genome size, gene order, codon usage bias, and GC-content to determine what mechanismscould have produced the great variety of genomes that exist today (for recent overviews, see Brown 2002; Sacconeand Pesole 2003; Benfey and Protopapas 2004; Gibson and Muse 2004; Reese 2004; Gregory 2005).Duplications play a major role in shaping the genome. Duplication may range from extension of short tandemrepeats, to duplication of a cluster of genes, and all the way to duplication of entire chromosomes or even entiregenomes. Such duplication's are probably fundamental to the creation of genetic novelty.Horizontal gene transfer is invoked to explain how there is often extreme similarity between small portions of thegenomes of two organisms that are otherwise very distantly related. Horizontal gene transfer seems to be commonamong many microbes. Also, eukaryotic cells seem to have experienced a transfer of some genetic material fromtheir chloroplast and mitochondrial genomes to their nuclear chromosomes.

Genome 125

References[1] Ridley, M. (2006). Genome. New York, NY: Harper Perennial. ISBN 0-06-019497-9[2] ScienceShot: Biggest Genome Ever (http:/ / news. sciencemag. org/ sciencenow/ 2010/ 10/ scienceshot-biggest-genome-ever. html),

comments: "The measurement for Amoeba dubia and other protozoa which have been reported to have very large genomes were made in the1960s using a rough biochemical approach which is now considered to be an unreliable method for accurate genome size determinations."

[3] http:/ / www. ornl. gov/ sci/ techresources/ Human_Genome/ faq/ compgen. shtml#genomesize

Further reading• Benfey, P.; Protopapas, A.D. (2004). Essentials of Genomics. Prentice Hall.• Brown, Terence A. (2002). Genomes 2. Oxford: Bios Scientific Publishers. ISBN 978-1-85996-029-5.• Gibson, Greg; Muse, Spencer V. (2004). A Primer of Genome Science (Second ed.). Sunderland, Mass: Sinauer

Assoc. ISBN 0-87893-234-8.• Gregory, T. Ryan (ed) (2005). The Evolution of the Genome. Elsevier. ISBN 0-12-301463-8.• Reece, Richard J. (2004). Analysis of Genes and Genomes. Chichester: John Wiley & Sons. ISBN 0-470-84379-9.• Saccone, Cecilia; Pesole, Graziano (2003). Handbook of Comparative Genomics. Chichester: John Wiley & Sons.

ISBN 0-471-39128-X.• Werner, E. (2003). "In silico multicellular systems biology and minimal genomes". Drug Discov Today 8 (24):

1121–1127. doi: 10.1016/S1359-6446(03)02918-0 (http:/ / dx. doi. org/ 10. 1016/ S1359-6446(03)02918-0).PMID  14678738 (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 14678738).

External links• UCSC Genome Browser (http:/ / genome. ucsc. edu) - view the genome and annotations for more than 80

organisms.• (http:/ / www. genomecenter. howard. edu/ )• Build a DNA Molecule (http:/ / learn. genetics. utah. edu/ content/ begin/ dna/ builddna/ )• Some comparative genome sizes (http:/ / www. genomenewsnetwork. org/ articles/ 02_01/ Sizing_genomes.

shtml)• DNA Interactive: The History of DNA Science (http:/ / www. dnai. org/ )• DNA From The Beginning (http:/ / www. dnaftb. org/ )• All About The Human Genome Project (http:/ / www. genome. gov/ 10001772)—from Genome.gov• Animal genome size database (http:/ / www. genomesize. com/ )• Plant genome size database (http:/ / www. rbgkew. org. uk/ cval/ homepage. html)• GOLD:Genomes OnLine Database (http:/ / www. genomesonline. org/ )• The Genome News Network (http:/ / www. genomenewsnetwork. org/ )• NCBI Entrez Genome Project database (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=genomeprj)• NCBI Genome Primer (http:/ / www. ncbi. nlm. nih. gov/ About/ primer/ genetics_genome. html)• GeneCards (http:/ / www. genecards. org/ )—an integrated database of human genes• BBC News - Final genome 'chapter' published (http:/ / news. bbc. co. uk/ 1/ hi/ sci/ tech/ 4994088. stm)• IMG (http:/ / img. jgi. doe. gov/ ) (The Integrated Microbial Genomes system)—for genome analysis by the

DOE-JGI• GeKnome Technologies Next-Gen Sequencing Data Analysis (http:/ / www. geknome. com/ )—next-generation

sequencing data analysis for Illumina and 454 Service from GeKnome Technologies.

Article Sources and Contributors 126

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Cytosol  Source: https://en.wikipedia.org/w/index.php?oldid=575699174  Contributors: A3camero, AThing, Alansohn, Albval, Alperen, Andres, Arcadian, Attys, Bensaccount, Bobo192,Bobomarch, Brainmuncher, Brichcja, Chichui, Chris the speller, Circeus, Clicketyclack, ClockworkSoul, Conversion script, Daycd, Dexter's Lab, Diberri, DrFO.Jr.Tn, Drahgo, Drclindsay,Drphilharmonic, Duncan.france, Enchanter, Fraggle81, Fuzzform, Gilliam, Gobonobo, Hectorthebat, Holaroger12345, Hydrogen Iodide, Ioan-Mihai Gale I, Ivan Bajlo, Iztwoz, Jared81, Jcw69,Jesse V., Jncraton, Jsayre64, Jusjih, Kevin Hughes, Khazar2, Korimi, Last Lost, LoneSeeker, Loodog, Lord of the Pit, M1ss1ontomars2k4, MER-C, Marek69, Marqueed, Marshman, Mav,Mgiganteus1, MichaK, Michael Devore, Mike Rosoft, Mike2vil, Miyagawa, MortimerCat, Mquiroz, NPrice, Narayanese, Nbauman, Noneforall, Nunh-huh, Onco p53, PDH, PFHLai, PaineEllsworth, Petter Trillkott, Quercus solaris, R. S. Shaw, RDBrown, Rama, Revery, Rhys, Rich Farmbrough, Rjwilmsi, RodC, Sanfranman59, Serephine, Shanel, Silvem, Some jerk on the Internet,StAnselm, Staszek Lem, TheAMmollusc, TheLedBalloon, TimVickers, Tombo, Tubarun, VictorianMutant, Wetman, Zundark, 132 anonymous edits

Cytoplasm  Source: https://en.wikipedia.org/w/index.php?oldid=582998639  Contributors: 129.128.164.xxx, 168..., 1exec1, 2D, 786azad, A3RO, Aaron north, Abc518, Ac352, Ace258,Acroterion, Adambro, Adan, Addshore, Adm820, Adrian.benko, Afctenfour, Ahoerstemeier, AlanD, Alansohn, AlexBlair812, Alexius08, AlexiusHoratius, Alias Flood, Allen3, Allens,Allstarecho, AllyUnion, AlphaEta, Alphachimp, Alphax, Altruism, Ampersand777, Anbu121, AndreaBear1208, Andykinosis, Animum, Antandrus, Anthere, Antonio Lopez, Apers0n,Appeltree1, Arakunem, Aram-van, Arcadian, Artaxiad, Arthena, Ashmt, Atif.t2, Austinpieschel, BD2412, Backslash Forwardslash, Banana04131, Barek, Bassbonerocks, Beetstra, Betamod,Blackcats, Blanchardb, Blood sliver, Blue520, Bluejhon, Bob rulz, Bobo192, Bogey97, Bomac, Bongwarrior, BorgQueen, Breakyunit, Bulba2036, CDN99, CaRzRlIfE, Calmer Waters, Caltas,Can't sleep, clown will eat me, CanadianLinuxUser, Capricorn42, CardinalDan, Cblair1234, Celestianpower, Cellmike07, Chamal N, Chris the speller, ChrisGualtieri, Chrislk02, Chupon, Cirt,ClarkMills, ClockworkSoul, Closedmouth, Cobett123, Cocytus, Cody allen tokarcik, Coffee, CommonsDelinker, Connormah, Conversion script, Coolidays, Cornischong, Courcelles,Crazymonkey1123, Cst17, Csörföly D, Cyclopose1, CzarB, DARTH SIDIOUS 2, DSRH, DVD R W, DVdm, Damnitsme, Daniel Case, Darth Panda, Darth demonbomb, Darthchess, Das Nerd,DasBub, Dawn Bard, Deckiller, Delldot, Delparnel, Denisarona, Dentalplanlisa, Deor, DerHexer, Derg4, Dhodges, DigitalCatalyst, Discospinster, DivineAlpha, Dmuth, Docboat, Doctor Hugh,Dogposter, Donner60, DoubleBlue, DrFO.Jr.Tn, Draeco, Drclindsay, Dspradau, Ducky1278, Dupz, Dynaflow, Dysepsion, Dysfunktion, E Wing, Ealex292, Ebenton, Ed Poor, Edwinstearns,Eleuther, Elia-thomas-zard, Ember of Light, Emw, EnTiKe, Enchanter, Enviroboy, Epbr123, Erianna, Everyking, Evil saltine, FallingRain123, Fama Clamosa, Ferengi, Finngall, Flavaflav1005,Fox Wilson, Funandtrvl, Fuzheado, Fvw, G3pro, GLaDOS, Gear head rsx, Geek302, George The Dragon, Georgette2, Giftlite, Ginsuloft, Gogo Dodo, GrahamColm, GrayFullbuster,Grendelkhan, Grim23, Gruw11, Gscshoyru, Guanaco, Gurch, Guy1890, Halmstad, Harvardprofessor1, Hatch68, Hayabusa future, Heywhatsgoingon, Himynameisnorm, Hordaland, Hornlitz,Htownsocal, Hulek, Husond, Hut 8.5, Hydrogen Iodide, II MusLiM HyBRiD II, IW.HG, Igoldste, Imaglang, Imessedthisup, Indon, Ioeth, Iridescent, IronGargoyle, Isfisk, Isopropyl, Itemirus,J.delanoy, JForget, JLaTondre, JWSchmidt, Jacek Kendysz, Jack007, Jadencampbell3, Jag123, Jarble, Jared81, Javert, Javierito92, Jay-Sebastos, JazzSong, Jcw69, Jdwoodalltx, Jesup, Jim1138,JimVC3, Jimp, Jlfuchs, John Cardinal, JohnArmagh, Jonathan Webley, Josh Cherry, Joshbuddy, Jossi, Josve05a, Juandev, Jusdafax, Kcox101, Kedi the tramp, Keelan1993, Keilana, Kelly Martin,Killiondude, Kimchi.sg, Kinkreet, Kipu2021, Kirachinmoku, Kirby Raccoon, Knsyknsy, Kopro002, Kosack, Kowey, Kubra, Kukini, LamilLerran, Larth Rasnal, LeaveSleaves, Lee S. 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Organelle  Source: https://en.wikipedia.org/w/index.php?oldid=583814020  Contributors: 090-chall, 168... DNA edit war, 1pezguy, 2004-12-29T22:45Z, 212.134.69.xxx, 28bytes, AVand,ActivExpression, Adenosine, Adrian J. Hunter, Alansohn, Alfie66, Amantine, Anclation, Andre Engels, Andy120290, Andycjp, Anomalocaris, Antionne1, Arcadian, Avoided, BKalesti,Beno1000, Bensaccount, Bernie Sanders' DNA, Bggoldie, Bhumiya, Bidabadi, Billare, Bio geekz, Biologos, Bjarki S, Blake-, Blanchardb, Blaxthos, Bleebie84105, Blue Danube, Bobo192,Boing! said Zebedee, Bomac, Bozartas, Breakyunit, Brian Crawford, CSWarren, Caladont, CanadianLinuxUser, CanisRufus, Capricorn42, Carba, Careless hx, Carhuly, Carmichael, Catgut,Cathardic, Cdcdoc, Chaos, Chaser, Chichui, Chizeng, Chris the speller, Ckatz, ClamDip, ClockworkSoul, Clohse17, Conversion script, Corrigen, Courcelles, Cp111, Cspurrier, Csutric, CsörfölyD, DVdm, Daniel5127, Dark Samus, DarkAudit, Darkwind, Darkwind6000, Debresser, Decumanus, Deflective, Deor, DerHexer, Dgw, Dietzel65, Discospinster, DivineAlpha, Dogposter, Dougswisher, Download, Drphilharmonic, Drsrisenthil, Dullhunk, Duncharris, Durova, Dwayne, Edittingdude, Efe, Elapied, Elfboy574, Enochlau, Epbr123, Eribro, Eric-Wester, Evanreyes, Excirial,Extrablue, Faradayplank, Farid2053, Ferengi, Forever Dusk, Fraggle81, Freakofnurture, FreeKresge, G3pro, Gabbe, George W Bush's DNA, Gholam, Giftlite, Gilliam, Ginsuloft,Glassofwateronthecounter, Gogo Dodo, GoingBatty, GrandpaDoc, Gustafave, Guyd, Hadal, Haeinous, Hair, Hal0 g33k101, Halmstad, Harry Reid's DNA, Hello32020, Hotcrocodile,Hurricane111, Hydrogen Iodide, II MusLiM HyBRiD II, IRP, IW.HG, Ilmari Karonen, Ilyanep, Intelati, Iridescent, Ixfd64, J.delanoy, JForget, JaGa, Jackol, Jarble, Jim.henderson, Jmcollier, JohnEnsign's DNA, John Owens' DNA, John the ripper, John254, Johnny Isakson's DNA, Jon Kyl's DNA, Jon Porter's DNA, Jonathanfu, JonathonSimister, JulianC, Jusdafax, Justinsomnia, KENSALAZAR'S DNA, KGasso, Kay Dekker, Kazkaskazkasako, Kazvorpal, Kelly Martin, KenEmerson, Kinaro, Kpjas, Kupirijo, Kurtispj, Kville105125, Kwamikagami, Kwiki, L'Aquatique,LadyofHats, LeeG, Leleleleleleleleleleleeee, Lexor, Lilceez, Lir, Livitup, Lordofflame212, Low-frequency internal, Lozeldafan, Lugia2453, Luna Santin, Macaddct1984, Mad Microbiologist,Magioladitis, Magnus Manske, Magog the Ogre, Marcelivan, MarkS, Martial75, Martious, Materialscientist, Mato, Matthew Yeager, Mav, Mentifisto, Mhking, MichaK, Michael Hardy,MichaelBillington, Micromagnets, Middlemanmaster, MidgleyDJ, Midgrid, Mikael Häggström, Mike2vil, Misscutie27, Mononomic, Monterey Bay, Mormegil, Mostermann, Mrpepsidrink,Mschel, N2e, Nakon, NawlinWiki, Necessary Evil, Nehrams2020, Neocrypticzero, New Jack Swing, NewEnglandYankee, Neøn, Nickptar, NilsTycho, OnePt618, PFHLai, Paul Foxworthy,Pauli133, Paxsimius, Pb30, Pepper, Philopp, PhnomPencil, Piano non troppo, Pinethicket, Plindenbaum, Postglock, Princess Clown, Prodego, Proofreader77, R. S. Shaw, RA0808, Rama's Arrow,Razor2988, Rcej, Ready, Realricanboy123, Reaper Eternal, Res2216firestar, Rettetast, Rexkim, Rhd, Riana, Rishaj, Rjwilmsi, Roemmdal, Ronhjones, Scjessey, Seegoon, Senator Palpatine,Sephiroth BCR, Shadowjams, Shakarun1, Shanes, Sharkface217, Shelly berkeley's DNA, Shirik, Shlomke, Skarebo, Skizzik, Slates22, Sludtke42, Smartiger, Snapish, Snigbrook, Snow Blizzard,Snowolf, Soliloquial, Soralin, Spamburgler, Steinsky, Stephenb, Stevenr123, Stwalkerster, Sunrise, Suriel1981, Svick, Sylverfysh, Synchronism, Tangotango, Td321, Ted Steven's DNA,Teknopup, Teles, Template namespace initialisation script, Tentinator, Tetigit, Tgeairn, The Anonymouse, The Thing That Should Not Be, Theccy, Thingg, Tide rolls, TimVickers, TobiasBergemann, Tohd8BohaithuGh1, Tom Delay's DNA, Tom Lougheed, TomasBat, Tombo, Tomgally, Tommy2010, Totoybrownpogi, TravisTX, Treygdor, Triwbe, Tryptofish, Tyrol5, Vacio,Vanished user 1234567890, Vrenator, WahreJakob, Wavelength, WereSpielChequers, Werieth, Widr, WikiDao, WikiFew, Wikieditor06, Wikipelli, Wondpook, Wouterstomp, Wtmitchell, X!,Yamamoto Ichiro, Yourexhalekiss, ZX81, Zzuuzz, 843 ,کاشف عقیل anonymous edits

Cell nucleus  Source: https://en.wikipedia.org/w/index.php?oldid=582434640  Contributors: 069952497a, 129.186.19.xxx, 1STstringcorner, 444et, 54gsze4ghz5, A D 13, AMK152, AShin1130, Aaron north, Acdx, Adenosine, Adriaan, Adrian.benko, Afctenfour, Aflumpire, Ahoerstemeier, Alcmaeonid, Alessandro f2001, Alexius08, Alicesteele, Allens, Altaïr, Anbu121, Andre Engels, Andy120290, AndyZ, Angelicskeleton, Anna Lincoln, Anrnusna, Antandrus, Arakunem, Aram-van, Aranea Mortem, Arcadian, Arthena, Artoasis, Avoided, BBBHHHCCCQQ, Barek, Bart133, Bela Bartoszek, BenJWoodcroft, Bensaccount, Bentogoa, Betacommand, Bethpage89, Bhadani, BigPimpinBrah, BillC, Billygoaty11, Bobo192, Bomac, Bongwarrior, Booksworm, Bragador, Brandonbart, Brettbarbaro, Brighterorange, Brion VIBBER, BruceBlaus, Brumski, Bryan Derksen, Bulldozer1203, CJLL Wright, CWii, Cacolantern, Caltas, Calvwag, Can't sleep, clown will eat me, CanadianLinuxUser, Capricorn42, Casper2k3, Catgut, Cdamama, Celestechang, Centrx, CephasE, Ceyockey, Chaos, Chastityb, Cheapshot202, Chino, Chizeng, Chris.heneghan, Chris857, ChrisGualtieri, Ckatz, ClickRick, ClockworkSoul, Closedmouth, Cmcnicoll, Cntras, Coelacan, ColbeagleTheEagle, Complex (de), Conclark12, Conversion script, Cool3, CopperKettle, Cryptophile, Cureden, DARTH SIDIOUS 2, DMacks, DRHagen, DVdm, Dan Wylie-Sears, Daniel Mietchen, DanielCD, Darkfight, Darth Mike, Darth Panda, Datofm, Dcooper, Debresser, Delldot, Demmy, Den fjättrade ankan, Deor, DerHexer, Dietzel65, Discospinster, Dl400198, Donarreiskoffer, Dosorio2012, DoubleBlue, Dr Aaron, DrMicro, Draicone, Drakemiral, Dreid1987, Drgarden, Drmies, Drphilharmonic, Dycedarg, Dysprosia, ERcheck, Echtoran, Editore99, Edward, Eeekster, Ehaag, Eleassar, Eleassar777, Ember of Light, EnSamulili, Epbr123, EuroCarGT, Everyguy, Evil saltine, Excirial, Fadedlight56, Fang Aili, Faradayplank, Fastily, Fiasco, FishingKing, Flurry1001, Flyer22, Forluvoft, Francine3, Freakofnurture, FrozenMan, Funandtrvl,

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Fvasconcellos, Fyrael, GAThrawn22, GT5162, Gaff, Gaius Cornelius, Gakusha, Ged UK, Gene Nygaard, Genericmister2000, Genericmister3000, GetAgrippa, Gfoley4, Ghiraddje, Giftlite,GillPer, Gilliam, Gimmetrow, Ginsuloft, Glagolev, GlassCobra, Godlord2, Gogo Dodo, Gracenotes, Graham87, Grahamec, Greg L, Gruzd, Gurch, Gwernol, Habj, Hadal, Hangjian, Hankston,Harrymph, Haydood23, Hazhk, Hdt83, Heero Kirashami, Hello32020, Hollisterfrk1, Hotcrocodile, Hughitt1, Hydrogen Iodide, Hypernite, II MusLiM HyBRiD II, Igoldste, Immunize,IncognitoErgoSum, Insanity Incarnate, Interiot, Irdepesca572, Iridescent, Irishguy, Isaac.holeman, Isfisk, Iste Praetor, IvanLanin, Iztwoz, J.delanoy, JForget, JNW, JWSchmidt, Jacobso4,JamesBWatson, Jamesx12345, Jamison Lofthouse, Jauerback, JavierMC, Jeff G., Jeffrd10, Jesse V., Jesserrro3, Jguard18, JimVC3, Jj137, Jncraton, JodyB, John, Joseph Solis in Australia, JoshGrosse, Juliancolton, Kaushlendratripathi, Kay Körner, Kazkaskazkasako, Kbh3rd, Keilana, Ken Gallager, Kg moin, Khazar2, Khmir2467, Khukri, Kidkidpie, King of Hearts, Kinglz, Kira1366,Klilidiplomus, Kowey, Koyaanis Qatsi, KrakatoaKatie, Krich, Kungming2, Kupirijo, La Pianista, LadyofHats, Lalsingh, Lbthrice, Leafyplant, LeaveSleaves, Leptictidium, Lerdthenerd, Leuko,Lexor, Lightdarkness, Lights, Lir, LittleOldMe, Littleghostboo, Llull, Locke7, Lopini, LovesMacs, LuigiManiac, Luna Santin, Luuva, MER-C, Macaddct1984, Magicwombat, Magnus Manske,Maitch, MarcoTolo, Marcsin, Marek69, Mark Arsten, Materialscientist, Matt Deres, Mattbr, Mayur, Meaghan, Mentisock, Mgiganteus1, MichaK, Michael Devore, Mifter, Mike2vil, Mild BillHiccup, Milotoor, Mindmatrix, Mindstalk, MisterSheik, Misza13, Modify, Mononomic, Moreschi, Mr.Bip, Mufka, MusikAnimal, Mutt Lunker, Nad, Nadav224, NawlinWiki, Nbauman,Neonegg, NerdyScienceDude, Neurolysis, NewEnglandYankee, Nick, Nick Number, NightWolf1298, Nihiltres, Nikkimaria, Ninjamatrixking, Nivix, No Guru, Nonagonal Spider, Nono64, Nsaa,O.Koslowski, Ocaasi, Ohsowskisc, Oleksii0, Omega Archdoom, Onebravemonkey, Opabinia regalis, Orphan Wiki, Outriggr, OverlordQ, Oxymoron83, P8ntballer1111, PDH, PFHLai, PM800,Pappucantdancesalla, Parhamr, Paul-L, Paxsimius, Peter, Peter Delmonte, Peter James, Peter-27, Peteruetz, Phantomsteve, Philip Trueman, Piast93, Pierpontpaul2351, Pinethicket, Pip2andahalf,Plantsurfer, Pluemaster, Pluma, Pootang123456789, Posterlogo, Preraraheart, Pro bug catcher, Professer Joseph, Proofreader77, Puchiko, Puffin, Pupster21, Pyrospirit, Quadpus, Quintote,QuiteUnusual, Qwyrxian, R. S. Shaw, RA0808, RadioFan, RandomP, Reaper Eternal, Reconsider the static, RedHillian, Reddy4me1994, Remember the dot, Reo On, Res2216firestar, RexNL,Reywas92, Rich Farmbrough, Richard D. LeCour, Rigby27, Rjwilmsi, Rking36, Rmosler2100, Robert Foley, RobertG, RockfangSemi, RodC, Rorro, Rory096, Rsundby, Rumping, RxS,SEUNGWAN, SMC, SMP, Sam00110101, Sammypkrs, Samsara, Samtheboy, SandyGeorgia, Satellizer, Sbaker100, SchfiftyThree, Schrodingerscat09, Scjessey, Sd2011wiki, Seaphoto, Seegoon,Seejyb, Selket, ServAce85, ShaiM, Shalom Yechiel, Shell Kinney, Shizhao, Shmget, Shoeofdeath, SidneyMorataya, Silvrous, SimonP, Sionus, Sirbonkers, Skelly247, SkyMachine, Slakr,Smartse, Snoyes, Soliloquial, Some jerk on the Internet, Someguy1221, SpaceFlight89, Sparkey01, Spencer, StAnselm, Steinsky, Stepa, Stephenb, Stevo5987, Streetfoo212, Stylodinesh, SummerSong, SuperHamster, Suruena, Syp, THEN WHO WAS PHONE?, Tameeria, Tapir Terrific, Tariqabjotu, Tavilis, Tbhotch, Teentje III, Tekks, Template namespace initialisation script, Tentinator,Terper, Thatotherperson, The Rambling Man, The Thing That Should Not Be, The wub, TheGWO, Thebestofall007, Thine Antique Pen, Thingg, Thomas MacAlister, Tide rolls, TimVickers,Titoxd, Tobias Bergemann, Tombomp, Tommy2010, TonyBallioni, Totoybrownpogi, Tranphuongthuy, Trevor MacInnis, Trusilver, Tryptofish, Two-Sixteen, Tycho, Ugen64, Uncle Dick, UserA1, Vald, Vanished user 39948282, Vary, Venullian, Versus22, VictorLucas, Vojtech.dostal, Vossman, Waltpohl, WarthogDemon, Wavelength, Wayne Slam, Webclient101, WereSpielChequers,Whale plane, Widr, WikipedianProlific, Wikipedosucklol2, Wikipedosucklol3, Wikipelli, Will Beback Auto, William Avery, Willking1979, Wimt, Winallfights1991, Winchelsea, Wknight94,Wouterstomp, Xanchester, Yahel Guhan, Yamamoto Ichiro, Yintan, Yug Kansara, Yuyudevil, Zahid Abdassabur, Zfr, Саша Стефановић, 1329 anonymous edits

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Ribosome  Source: https://en.wikipedia.org/w/index.php?oldid=583315933  Contributors: 209.234.79.xxx, A8UDI, AAM, Achim Raschka, Acroterion, AdjustShift, AeonicOmega, Agathman,Ahoerstemeier, Aiken drum, Aitias, Akriasas, Alansohn, Ale jrb, Alexius08, Alexllew, Alfie66, Alksub, Amatulic, Ananthkamath1995, Andre Engels, Andrewrp, Andy pyro, Andy4789,Anomalocaris, Anonymous Dissident, Antandrus, Arakunem, Aram-van, Arcadian, ArchDaemon, Arkuat, Arnoldlcl, Atif.t2, Az1568, Aznshark4, Banpei, Banus, BarretB, Bart133,Bendover12345, Bensaccount, Benzenetoaster, Betacommand, Billybutterworthreborn, Biodoc546, Blaxthos, Blood sliver, Bluesquareapple, Bobo192, Boppet, Brambleclawx, Branddobbe,Breckp, Brianmurphy22, Brim, Burntsauce, CKlunck, Caladont, Can't sleep, clown will eat me, CanadianLinuxUser, Captaincollect1970, CardinalDan, Carstensen, Cela, Cerealkiller13, Chaos,CharlesC, Chrisahn, Chrishmt0423, Christian List, ClarkFreifeld, Cless Alvein, Climax Void, Closedmouth, CommonsDelinker, Connormah, Conversion script, Cph3992, CryptoDerk,Crystallina, Cstillabower, Cypher3c, Czernilofsky, D, D. 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Vesicle (biology and chemistry)  Source: https://en.wikipedia.org/w/index.php?oldid=583252956  Contributors: %xxtrackingcookiexx%, 168..., A412, Achowat, Adambiswanger1, Addihockey10, AlB, Alansohn, Alexdubr, Amr94, Anafar, AnnaP, AquamarineOnion, Aram-van, Arcadian, Audriusa, Aviados, Ayacop, BabbaQ, Banus, Ben Robert, Bender235, Bensaccount, Blaxthos, Boing! said Zebedee, CanadianPenguin, CanisRufus, Centrx, Chaos, Clone89, Cmdrjameson, Connormah, Conversion script, Courcelles, Cyclonenim, DARTH SIDIOUS 2, Dan Gluck, Daycd, Demitsu, DerHexer, Diberri, Difu Wu, Discospinster, Dmontesano, Dogposter, Donner60, Durova, Eleassar777, Epbr123, Ericdiluccio, Fenteany, Fieldday-sunday, Flyguy649, Flyingtoaster1337, Foobar, Forty Seven Nine, Fryed-peach, GB fan, Giftlite, Gurch, Gyll, Hadal, Hakan Kayı, Hallenrm, HamburgerRadio, Hattiey, Heron, Hodja Nasreddin, Jackfork, Jehochman, Jesse V., Jet the Nerd, Jfurr1981, Jguk, Jj137, John254, Jolivio, Jwadeg, Kinglz, Kirankumar1234, KoshVorlon, Kristenhug, Lexor, Lir, Lucky 6.9, Lugia2453, MCGrief, Magioladitis, Magnus Manske, Mark Arsten, Martarius, Martin451, Materialscientist, Mcmillin24, Mderezynski, Mean as custard, Mendaliv, Methcub, MichaK, Mikael Häggström, MisterSquirrel, My very best wishes, Mysterytrey, Narayanese, Nathan, Nilfanion, Nipisiquit, Nmedard, Oddbodz, OlEnglish, PFHLai, Patstuart, Phantomsteve, Philip Trueman, Pinethicket, Plantsurfer, Proofreader77, Qtnguyen92683, RDBrown, Rich Farmbrough, RickK, Rittard, Robert M. Hunt, RockMagnetist, Rotational, Rozzychan, SMC, Scoops, Seaphoto, Shadowjams,

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Skizzik, Sky380, Slon02, Smartse, Sminthopsis84, Specs112, SpeedyGonsales, Spencer, SriMesh, Sriharsh1234, Steinsky, Stepa, Stevage, Stwalkerster, TJJFV, Template namespace initialisationscript, The Anome, The Utahraptor, TheGrimReaper NS, Thexmanlight, Thingg, Tide rolls, TimVickers, Tpbradbury, Travis dave@hotmail.com, Traxs7, Tryptofish, Ukexpat, Unused000701,WLU, Wavelength, WriterHound, 395 anonymous edits

Endoplasmic reticulum  Source: https://en.wikipedia.org/w/index.php?oldid=583638406  Contributors: .:Ajvol:., 168..., 23th, 27jacob27, 6r6r6muyr6uh, 97198,;jdfnudiudsacfjamcaroueafh;ndjk;h, A.amitkumar, Aaron Schulz, Aaron98990, Aaw37, Abc518, Academic Challenger, Acather96, Achim Raschka, ActivExpression, Adrian J. Hunter,Adrian.benko, Ahoerstemeier, Aleenf1, Alemily, Alex.tan, Alice D'Rozario, Alksub, Allen3, Allstarecho, Almar881, AlphaEta, Altaïr, Anaxial, Andrewpmk, Andy M. 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Centrosome  Source: https://en.wikipedia.org/w/index.php?oldid=580954414  Contributors: AdjustShift, Adrian.benko, Aleenf1, Alexei Kouprianov, Alperen, Anclation, Andre Engels,Arcadian, Avish2217, Bendzh, Blue Danube, Brainmachine, Brim, Calvin08, Cellbiology1, Ceyockey, Chichui, Chiefboz, ChrisDaniel58, Colababy, CommonsDelinker, Crystalcat55, D-Mob362,DBigXray, DMacks, DVdm, Dawn08, Dgw, Dougmerritt, Drbork, Duckyinc2, Empco, Epbr123, Epingchris, Eric Shalov, Faithlessthewonderboy, Faizan, Flying Canuck, Fotakos, Frietjes,Ggonnell, Hephaestos, Imilan, Instinctzz, Irestall, Iridescent, Irradiator, Itzrich5, JHunterJ, Jacyanda9, Jag123, Jcvamp, Jenks, Jumpingrat, Ka Faraq Gatri, Kelly Martin, Kelvinsong, Kinu,Kupirijo, La goutte de pluie, Lankenau, M1ss1ontomars2k4, Magioladitis, Manop, Merlintrix, MichaK, Minghong, Mortense, Mouce101, Munita Prasad, Narayanese, Naturespace,NightWolf1298, Ninawow, Nono64, Norm, Northamerica1000, OS2Warp, PFHLai, Pinethicket, Polypompholyx, Quintote, Qwaserdf25, Ratiocinate, Redfootedhurricane, Regidg,RenamedUser01302013, Rexodus, Rjwilmsi, RodC, Rogerburks, Seamstresserin, Sentriclecub, Serasuna, Shadowjams, SimonMayer, Siriuswhite1, Skunkboy74, Snowolfd4, Sowlos, Spjelgus,Squids and Chips, T@nn, Tabascoj, Tameeria, Thatguyflint, Thegreatgrabber, Touch Of Light, Twooars, Vanya Eccles, WAvegetarian, Wenli, Widr, WriterHound, ふ わ ふ わ, 175 anonymousedits

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Sobreira Abrahão, Ferengi, FerzenR, Firsfron, Fish and karate, Flavonoid, For7thGen, Forluvoft, Frap, Fuzheado, GSlicer, Genome biologist KS, Genometer, Geoff, George Church, GeorgeGastin, Giftlite, Gilliam, Gitana127, Glenn, Gogo Dodo, Grmagne, Gsp, Gulmammad, Haeinous, HangingCurve, Hawkeye356, Haywardlc, Herbee, Heron, Hgamboa, Holycow32989, Hubcap21,Huttarl, Immunize, Indianpjn, Insanity Incarnate, InternetMeme, Ioverka, Iridescent, IstvanWolf, Iwilcox, JH-man, Jaums, Jbkgiants, Jenks, Jesse V., Jim1138, Jo3sampl, Joconnol, JohnMackenzie Burke, Johntex, Johnuniq, JongPark, Jonverve, Joshafina, Julesd, KGasso, Kaarel, Kafziel, Kaiwen1, Karlthegreat, Katieh5584, Kbradnam, Kducey, Keilana, Kylic, LC, Lambiam,Larryisgood, Laurinavicius, Lavateraguy, Lbeaumont, Lexor, Lightmouse, Llull, Loren36, Lova Falk, Madeleine Price Ball, Magnus Manske, Manchester123456789, Marian, MarionADelgado,Marj Tiefert, Mark R Johnson, MartinPoulter, MartinezMD, Matt.whitby, Matt11111111, Miciah, Mikael Häggström, Mindmatrix, Mindspillage, Minimice, Mkh388, Mogism, Moink, Moorelin,Moreschi, MrPMonday, MusikAnimal, Mxn, Namazu-tron, NawlinWiki, Netrapt, Nick Thompson, Niteowlneils, No Guru, Nono64, Northamerica1000, NotWith, Ohnoitsjamie,Onceonthisisland, Onco p53, Oneiros, Ontarioboy, Open2universe, Orange Suede Sofa, Ottava Rima, Oxwil, PDH, PSimeon, Paranthaman, Pathh, Patho, Paul Abrahams, Peteruetz, Pewwer42,Pgan002, Pifactorial, Polyhedron, PradeepArya1109, Purnajitphukon, PuzzletChung, Pvosta, Quadell, Quintote, RJASE1, Raccoon Fox, Ramujana, Randomaperry, Realfoxxx, Reinyday, Rhetth,Rich Farmbrough, Rich.lewis, Rjwilmsi, Rkitko, Ronz, Rosieredfield, SEWilco, Sabedon, Sabisteb, Sampsonjk, Samsara, Savant1984, ScAvenger lv, Scarian, Schutz, Scilit, Scwlong, SeanMack,Seglea, Sentausa, Several Times, Shinkolobwe, Shoefly, Shogatetus, Shrimp wong, Silvrous, Sjjupadhyay, Skier Dude, Sluzzelin, Smalljim, Smartse, Snek01, SocialContext, Specs112,SpuriousQ, Steinsky, Stephen Turner, SteveChervitzTrutane, Stevertigo, Stroppolo, Stwalkerster, Summer Song, Sumukal, Svetovid, Tareqiu, Taxman, The Rationalist, The Storm Surfer,TheAMmollusc, TheAlphaWolf, Thecheesykid, Thorwald, TimVickers, Tomaschwutz, Tomyhoi, Tosendo, Tpbradbury, TrenSur, True Pagan Warrior, Trusilver, Turnstep, Two hundred hum,Vanderesch, Vasi31, Veryhuman, Vipinhari, Vrenator, Vsmith, WadeSimMiser, Waerfeles, Wavelength, Wenfuli, Wet dog fur, Whosasking, Wikiborg, Will Beback Auto, Woodsrock,Woohookitty, Wootini, Xmteam, YaguchiA, Youandme, Youssefa, Youssefsan, Zakarps, Zashaw, ZeWrestler, Zfr, Zundark, Σ, 349 anonymous edits

Image Sources, Licenses and Contributors 133

Image Sources, Licenses and ContributorsFile:Wilson1900Fig2.jpg  Source: https://en.wikipedia.org/w/index.php?title=File:Wilson1900Fig2.jpg  License: Public Domain  Contributors: Edmund Beecher WilsonFile:celltypes.svg  Source: https://en.wikipedia.org/w/index.php?title=File:Celltypes.svg  License: Public Domain  Contributors: Science Primer (National Center for Biotechnology Information).Vectorized by Mortadelo2005.Image:Average prokaryote cell- en.svg  Source: https://en.wikipedia.org/w/index.php?title=File:Average_prokaryote_cell-_en.svg  License: Public Domain  Contributors: Mariana RuizVillarreal, LadyofHatsImage:Animal cell structure en.svg  Source: https://en.wikipedia.org/w/index.php?title=File:Animal_cell_structure_en.svg  License: Public Domain  Contributors: LadyofHats (Mariana Ruiz)Image:Plant cell structure svg.svg  Source: https://en.wikipedia.org/w/index.php?title=File:Plant_cell_structure_svg.svg  License: Public Domain  Contributors: LadyofHats (Mariana Ruiz)File:Blausen 0208 CellAnatomy.png  Source: https://en.wikipedia.org/w/index.php?title=File:Blausen_0208_CellAnatomy.png  License: Creative Commons Attribution 3.0  Contributors:User:BruceBlausFile:DAPIMitoTrackerRedAlexaFluor488BPAE.jpg  Source: https://en.wikipedia.org/w/index.php?title=File:DAPIMitoTrackerRedAlexaFluor488BPAE.jpg  License: Creative CommonsAttribution-Sharealike 3.0  Contributors: IP69.226.103.13Image:Endomembrane system diagram no text nucleus.png  Source: https://en.wikipedia.org/w/index.php?title=File:Endomembrane_system_diagram_no_text_nucleus.png  License: Publicdomain  Contributors: Peter Znamenskiy at en.wikipediaImage:Three cell growth types.png  Source: https://en.wikipedia.org/w/index.php?title=File:Three_cell_growth_types.png  License: GNU Free Documentation License  Contributors:User:Bevo, User:JWSchmidtImage:Proteinsynthesis.png  Source: https://en.wikipedia.org/w/index.php?title=File:Proteinsynthesis.png  License: Public Domain  Contributors: Incnis Mrsi, Laikayiu, Torsch, 1 anonymouseditsFile:Stromatolites.jpg  Source: https://en.wikipedia.org/w/index.php?title=File:Stromatolites.jpg  License: Public Domain  Contributors: P. 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Goodsell, RCSBProtein Data Bank Original uploader was TimVickers at en.wikipediaImage:10 large subunit.gif  Source: https://en.wikipedia.org/w/index.php?title=File:10_large_subunit.gif  License: Public Domain  Contributors: Animation by David S. Goodsell, RCSB ProteinData Bank Original uploader was TimVickers at en.wikipedia

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File:DNA replication en.svg  Source: https://en.wikipedia.org/w/index.php?title=File:DNA_replication_en.svg  License: Public Domain  Contributors: LadyofHats Mariana RuizImage:Nucleosome1.png  Source: https://en.wikipedia.org/w/index.php?title=File:Nucleosome1.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: User:SpletteFile:Lambda repressor 1LMB.png  Source: https://en.wikipedia.org/w/index.php?title=File:Lambda_repressor_1LMB.png  License: GNU Free Documentation License  Contributors: Originaluploader was Zephyris at en.wikipediaFile:EcoRV 1RVA.png  Source: https://en.wikipedia.org/w/index.php?title=File:EcoRV_1RVA.png  License: GNU Free Documentation License  Contributors: Original uploader was Zephyrisat en.wikipediaFile:Holliday Junction.svg  Source: https://en.wikipedia.org/w/index.php?title=File:Holliday_Junction.svg  License: Public Domain  Contributors: derivative work:File:Holliday junction coloured.png  Source: https://en.wikipedia.org/w/index.php?title=File:Holliday_junction_coloured.png  License: GNU Free Documentation License  Contributors:Original uploader was Zephyris at en.wikipediaFile:Chromosomal Recombination.svg  Source: https://en.wikipedia.org/w/index.php?title=File:Chromosomal_Recombination.svg  License: Creative Commons Attribution 2.5  Contributors:David Eccles (Gringer)File:DNA nanostructures.png  Source: https://en.wikipedia.org/w/index.php?title=File:DNA_nanostructures.png  License: Creative Commons Attribution 2.5  Contributors: (Images were kindlyprovided by Thomas H. LaBean and Hao Yan.)File:Maclyn McCarty with Francis Crick and James D Watson - 10.1371 journal.pbio.0030341.g001-O.jpg  Source:https://en.wikipedia.org/w/index.php?title=File:Maclyn_McCarty_with_Francis_Crick_and_James_D_Watson_-_10.1371_journal.pbio.0030341.g001-O.jpg  License: Creative CommonsAttribution 2.5  Contributors: Marjorie McCartyFile:Symbol template class.svg  Source: https://en.wikipedia.org/w/index.php?title=File:Symbol_template_class.svg  License: Public Domain  Contributors: AnomieFile:NHGRI human male karyotype.png  Source: https://en.wikipedia.org/w/index.php?title=File:NHGRI_human_male_karyotype.png  License: Public Domain  Contributors: Courtesy:National Human Genome Research InstituteFile:Genome size vs number of genes.svg  Source: https://en.wikipedia.org/w/index.php?title=File:Genome_size_vs_number_of_genes.svg  License: Creative Commons Attribution-Sharealike3.0  Contributors: User:Estevezj

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