Apo lipoproteins structure and function

Name :Eman abd el raouf ahmed

Under supervision :Prof. Dr.Magda Megahed

Definition

Apo lipoproteins are the protein components of lipoproteins, the lipid–protein complexes responsible for transporting lipids in the blood. They may have additional specialized functions that are encoded by their genes..

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structure

Lipoproteins are spherical (VLDL, LDL, HDL) in shape with a core of non-polar lipids, triacylglycerols and cholesterol esters, and a surface monolayer, consisting of apoproteins, phospholipids and non-esterified cholesterol, which serves to present a hydrophobic face to the aqueous phase

Classification the main groups are classified as chylomicrons (CM),

very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL) and high-density lipoproteins (HDL), based on the relative densities of the aggregates on ultracentrifugation.

these classes can be further refined by improved separation procedures, and intermediate-density lipoproteins (IDL) and subdivisions of the HDL (e.g. HDL1, HDL2, HDL3 and so forth) are often defined, and each of these may have distinctive apoprotein compositions and biological properties that are relevant to cardiovascular disease.

Composition and structureLipoproteins are complex aggregates of lipids and proteins that

render the lipids compatible with the aqueous environment of body fluids and enable their transport throughout the body of all vertebrates and insects to tissues where they are required.

Lipoproteins are synthesized mainly in the liver and intestines. Within the circulation, these aggregates are in a state of constant flux, changing in composition and physical structure as the peripheral tissues take up the various components before the remnants return to the liver.

structure

Apo B100 and apo B48 large and water-insoluble they are the only non-exchangeable apoproteins, which are assembled into triacylglycerol-rich lipoproteins with their lipid components in the intestines or liver.

Cholesterol esters are required for proper folding of apo B. With 4536 amino acid residues, apoB100 is one of the largest monomeric proteins known; apo B48 represents the N-terminal 48% of apo B100.

From genes to proteins Structural organization of the human Apo lipoprotein (Apo) A‐I, A‐II, A‐IV,

C‐I, C‐II, C‐III and E genes. The wide bars represent the exons and are divided into several regions: the open bars at the two ends represent the 5′ and 3′ un translated regions; the hatched bars, the signal peptide regions; and the solid bars, the mature peptide regions of the respective genes.

THE DISTRIBUTION OF APOLIPOPROTEIN E GENOTYPE

• Apolipoprotein E (ApoE) is encoded by the codominant alleles ε2, ε3, and ε4, resulting in 6 bi-allelic genotypes

• The corresponding protein isoforms differ in their lipoprotein receptor affinity, antioxidant activity, and inflammation modulatory properties

• APOE ε4 carriership is associated with an increased risk of atherosclerosis and dementia

• Approximately 65%–75% of patients with Alzheimer's disease carry the ε4 allele

• http://aje.oxfordjournals.org/content/early/2015/01/21/aje.kwu442

physical propertiesThe physical properties of Apo proteins enable them to bind readily at the interface between water and phospholipids, and specifically they bind to the phospholipids on the surface of the lipoproteins. In effect, this outer shell of amphipathic lipids and proteins solubilizes the hydrophobic lipid core in the aqueous environment. http://lipidlibrary.aocs.org/Lipids/lipoprot/index.htm

Physical properties and lipid compositions of lipoprotein classes.

Types according to Molecular weight

Apo A1 is the main protein component of HDL, and is synthesised within the liver

(70%) and intestine (30%). It is a 28-kDa single polypeptide consisting of 243-amino acids, which has no disulfide linkages or glycosylation. Apart from the 44 amino acid N-terminal region, the protein is arranged as eight α-helical segments of 22 amino acids with two 11-mer repeats.

Apo A2 is the second most important HDL apolipoprotein, and it exists as a homodimer with two polypeptide chains, each 77 amino acids in length and linked by a disulfide bond.

Human apo A4 is the largest member of the exchangeable apolipoproteinfamily and is a 376-amino acid glycoprotein, which is synthesised in intestinal enterocytes and secreted as a constituent of chylomicrons

Apo protein(a) is an Adhesive ProteinThe apo(a) molecule contains the arginine-glycine-aspartate sequence

characteristic of adhesive proteins

Properties such as organ morphogenesis, differentiation, and growth have recently been discovered to be associated with a number of proteins present in the extracellular matrix and the blood, such as fibronectin, collagen, laminin, vitronectin, osteopontin including also coagulation factors such as fibrinogen .These ‘adhesive proteins’ contain a characteristic amino-acid sequence: arginine-glycine-aspartate (RGD), by means of which they interact with integrins, a family of cell surface receptors for adhesive proteins.

Detection of apo(a) in human sperm

o When human sperm was analysed in our laboratory, both the seminal plasma and the cellular fraction were found to contain apo(a).

o We could not detect any apo B associated with this apo(a).

The role of the adhesive protein apo(a) under pathological conditions

Apo(a) co-ordinates the interaction between cellular systems and the extracellular matrix during repair processes. Apo(a) is involved in tissue reformation during acute repair processes such as wound-healing .

They interact specifically with cellular systems such as monocytes, T cells as well as thrombocytes and thereby play a critical role in inflammatory, infectious, hemostatic and many other processes

The elevation of ap(a) plasma levels as established for cancer, cardiovascular, inflammatory and many other diseases is additional confirmation for this concept.

Apo B

is a protein that is involved in the metabolism of lipids and is the main protein constituent of lipoproteins such as very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL, the "bad cholesterol"). Concentrations of apo B tend to mirror those of LDL-C.

Apo B levels may be ordered to monitor the effectiveness of lipid treatment as an alternative to non-HDL-C (non-HDL-C is the total cholesterol concentration minus the amount of HDL).

Where is the APOB gene located?

Cytogenetic Location: 2p24-p23

Molecular Location on chromosome 2

the normal function of the APOB gene

The APOB gene provides instructions for making two versions of the apolipoprotein B protein, a short version called apolipoprotein B-48 and a longer version known as apolipoprotein B-100. Both of these proteins are components of lipoproteins, which are particles that carry fats and fat-like substances (such as cholesterol) in the blood.

Apolipoprotein B-48 is produced in the intestine, where it is a building block of a type of lipoprotein called a chylomicron. As food is digested after a meal, chylomicrons are formed to carry fat and cholesterol from the intestine into the bloodstream. Chylomicrons are also necessary for the absorption of certain fat-soluble vitamins such as vitamin E and vitamin A.

How are changes in the APOB gene related to health conditions?

More than 90 mutations in the APOB gene have been found to cause familial hypobetalipoproteinemia (FHBL), a disorder that impairs the body's ability to absorb and transport fat. Most APOB gene mutations that cause FHBL lead to the production of apolipoprotein B that is abnormally short.

hypercholesterolemia - caused by mutations in the APOB gene

At least five mutations in the APOB gene are known to cause a form of inherited hypercholesterolemia called familial defective apolipoprotein B-100 (FDB).

This condition is characterized by very high levels of cholesterol in the blood and an increased risk of developing heart disease. Each mutation that causes this condition changes a single protein building block (amino acid) in a critical region of apolipoprotein B-100.

What does the test result mean?Abnormal levels of apo B can also be caused by underlying conditions or other factors (secondary causes). Increased levels of apo B are seen, for example, in:

Diabetes

Use of drugs such as: androgens, beta blockers, diuretics, progestins (synthetic progesterones)

Hypothyroidism

Nephrotic syndrome (a kidney disease)

Pregnancy (levels increase temporarily and decrease again after delivery)

Apo B levelsmay be decreased with any condition that affects lipoprotein

production or affects its synthesis and packaging in the liver. Lower levels are seen with secondary causes such as:

Use of drugs such as: estrogen (in post-menopausal women), lovastatin, simvastatin, niacin, and thyroxineHyperthyroidismMalnutritionReye syndromeWeight reductionSevere illnessSurgeryCirrohsisAn increased ratio of apo B to apo A-I may indicate a higher risk of developing CVD.

http://labtestsonline.org/understanding/analytes/apob/tab/test/

APO E is an O-linked glycoprotein in three isoforms

and is synthesised by many tissues, including liver, brain, adipose tissue, and artery wall, but most is present in plasma lipoproteins derived primarily from the liver.

The function of APO E Apolipoprotein E has many functions in the body. When it is synthesized by the liver

as part of VLDL it functions in the transport of triglycerides to the liver tissue. It is also incorporated into HDL (as HDL-E) and functions in cholesterol distribution among cells. It is also incorporated into intestinally synthesized cholymicrons and transports dietary triglycerides and cholesterol.

Apolipoprotein E is synthesized in several areas of the body. Approximately three-fourths of the plasma apo-E is synthesized in the liver. Liver apo-E is produced primarily by hepatic parenchymal cells, and it becomes a component of VLDL. The brain also produces a large amount of apo-E.

http://wwwchem.csustan.edu/chem4400/SJBR/Dawn971.htm

Isoforms of APO E There are three different isoforms of apolipoprotein E: apo-E 2, apo-E 3, And apo-E 4.

Apo-E 3 is the parent form and all others are compared to it. Apo-E 2 is different from apo-E 3 because a cysteine is substituted for arginine at residue 158. Apo-E 2 is associated with Type III Hyperproteinemia (where there is an excess of protein in the blood plasma) and it does not bind to the lipid receptor.

http://wwwchem.csustan.edu/chem4400/SJBR/Dawn971.htm

Apo Dis atypical in that it is very different in structure from other apolipoproteins, and it is expressed widely in mammalian tissues (most others are produced mainly in liver and intestine). In plasma, it is present mainly in HDL and to a lesser extent in LDL, where it may function as a multi-ligand binding protein capable of transporting small hydrophobic molecules such as arachidonic acid, steroid hormones, and cholesterol for metabolism or signalling.

http://www.uniprot.org/uniprot/P05090

references(links)http://my.americanheart.org/professional/ScienceNews/Lipids-Lipoproteins-and-Apolipoproteins-as-Risk-Markers-of-Myocardial-Infarcti_UCM_466004_Article.jsp

http://www.ncbi.nlm.nih.gov/pubmed/25848795

http://www.ncbi.nlm.nih.gov/pubmed/25633982

http://www.isa-2015.com/program/tracks/

http://www.patient.co.uk/doctor/Apolipoproteins.htm

http://www.annualreviews.org/doi/abs/10.1146/annurev-neuro-071013-014300

http://onlinelibrary.wiley.com/doi/10.1111/j.1532-5415.1997.tb03211.x/full

http://www.atsjournals.org/doi/abs/10.1164/rccm.201411-1990OC#.VVhn67mqqko

References:http://www.ncbi.nlm.nih.gov/pubmed/6099394

http://www.ncbi.nlm.nih.gov/pubmed/15891389

http://www.ncbi.nlm.nih.gov/pubmed/11518754

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http://www.nextprot.org/db/entry/NX_P04114

http://www.ncbi.nlm.nih.gov/gene/347

http://www.biovision.com/apo-d-human-recombinant-3157.html

http://www.ncbi.nlm.nih.gov/gene?cmd=Retrieve&dopt=full_report&list_uids=347

http://www.uniprot.org/uniprot/P04114