Lipids & Membranes. Lipids Lipids are non-polar (hydrophobic) compounds, soluble in organic...

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Transcript of Lipids & Membranes. Lipids Lipids are non-polar (hydrophobic) compounds, soluble in organic...

  • Slide 1
  • Lipids & Membranes
  • Slide 2
  • Lipids Lipids are non-polar (hydrophobic) compounds, soluble in organic solvents. Most membrane lipids are amphipathic, having a non-polar end and a polar end. Fatty acids, the simplest lipids, consist of a hydrocarbon chain with a carboxylic acid at one end. an 16-C fatty acid: CH 3 (CH 2 ) 14 - COO - Non-polar polar
  • Slide 3
  • 14:0 myristic acid 16:0 palmitic acid 18:0 stearic acid 18:1 cis 9 oleic acid 18:2 cis 9,12 linoleic acid 18:3 cis 9,12,15 -linonenic acid 20:4 cis 5,8,11,14 arachidonic acid 20:5 cis 5,8,11,14,17 eicosapentaenoic acid Abbreviated notation for a 16-C fatty acid with one cis double bond between carbons 9 &10 is 16:1 cis 9. Some examples:
  • Slide 4
  • Most naturally occurring fatty acids have an even number of carbon atoms. There is free rotation about C-C bonds in a fatty acid, except at a double bond. Each cis double bond causes a kink in the chain. Rotation about other C-C bonds would permit a more linear structure than shown above, but with a kink. Double bonds in fatty acids are usually have the cis configuration.
  • Slide 5
  • Glycerophospholipids Glycerophospholipids (phosphoglycerides), are common constituents of cellular membranes. They have a glycerol backbone. Hydroxyls at C1 & C2 are esterified to fatty acids. An ester forms when a hydroxyl reacts with a carboxylic acid, with loss of H 2 O.
  • Slide 6
  • Phosphatidate The simplest glycerophospholipid is phosphatidate, in which fatty acids are esterified to hydroxyls on C1 & C2, while the C3 hydroxyl is esterified to P i.
  • Slide 7
  • In most glycerophospholipids (phosphoglycerides), P i is in turn esterified to OH of a polar head group ( X ), e.g.: serine, choline, ethanolamine, glycerol, or inositol. The 2 fatty acids tend to be non-identical. They may differ in length and/or the presence/absence of double bonds.
  • Slide 8
  • Phosphatidylcholine, with choline as polar head group, is an example of a glycerophospholipid. It is a common membrane lipid.
  • Slide 9
  • Phosphatidylinositol, with inositol as polar head group, is another example of a glycerophospholipid. In addition to being a membrane lipid, phosphatidyl inositol has roles in cell signaling.
  • Slide 10
  • Glycerophospholipid Each glycerophospholipid includes a polar region: glycerol, carbonyl of fatty acids, P i, & polar head group ( X ) 2 non-polar hydrocarbon tails of fatty acids (R 1, R 2 ). Such an amphipathic lipid is often represented as at right.
  • Slide 11
  • The amino group of sphingosine can form an amide bond with a fatty acid carboxyl to yield a ceramide. Ceramides usually include a polar head group, esterified to the terminal OH of the sphingosine. Sphingolipids are derivatives of the lipid sphingosine, which has a long hydrocarbon tail, and a polar domain that includes an amino group.
  • Slide 12
  • Sphingomelin, with a phosphocholine head group, is similar in size and shape to the glycerophospholipid phosphatidyl choline. Sphingomyelin, a ceramide with a phosphocholine or phosphethanolamine head group, is a common constituent of plasma membranes
  • Slide 13
  • Gangliosides, which have complex oligosaccharide head groups, are often found in the outer leaflet of the plasma membrane bilayer, with sugar chains extending out from the cell surface. Polar head groups of sphingolipids (ceramides):
  • Slide 14
  • Cholesterol Cholesterol has a rigid ring system and a short branched hydrocarbon tail. It is largely hydrophobic, but has one polar group, a hydroxyl, making it amphipathic. Cholesterol is found in membranes, and is the precursor for synthesis of steroid hormones and vitamin D.
  • Slide 15
  • Amphipathic lipids form complexes in which polar regions are in contact with water and hydrophobic regions away from water. Depending on the lipid and its concentration, possible molecular arrangements include: A monolayer at an air/water interface. Various micelle structures. A spherical micelle is a stable configuration for amphipathic lipids with a conical shape, such as fatty acids. A bilayer. This is the most stable configuration for amphipathic lipids with a cyllindrical shape, e.g., phospholipids.
  • Slide 16
  • In the liquid crystal state, hydrocarbon chains of phospholipids are disordered and in constant motion. At low temperature, bilayer phospholipids may undergo transition to a crystalline state in which fatty acid tails are fully extended, packing is highly ordered, & van der Waals interactions are maximal. Kinks in fatty acid chains, due to cis double bonds, interfere with packing of lipids in the crystalline state. Thus double bonds inhibit transition to the crystalline state, & lower the phase transition temperature. Membrane fluidity: The interior of a lipid bilayer is normally highly fluid.
  • Slide 17
  • Cholesterol inserts into bilayer membranes with its OH adjacent to polar phospholipid head-groups, and its hydrophobic ring system adjacent to fatty acid chains of phospholipids. Being slightly shorter than a phospholipid, cholesterol extends not quite to the center of the bilayer. Cholesterol inhibits transition from liquid crystal to crystalline state, because the rigid cholesterol ring interferes with close packing of phospholipid fatty acid tails. However the rigid cholesterol makes the membrane somewhat less fluid.
  • Slide 18
  • There are 2 strategies by which phase changes of membrane lipids are avoided: Cholesterol is abundant in membranes, such as plasma membranes, that include many lipids with long-chain saturated fatty acids. Cholesterol blocks transition to the crystalline state. Membranes that lack cholesterol, e.g., mitochondrial inner membrane, consist mainly of phospholipids whose fatty acids include one or more double bonds. The double bonds lower the melting point to below physiological temperature.
  • Slide 19
  • Cellular membranes contain a mixture of lipids. The fatty acid moiety of sphingolipids tends to be saturated. Glycerophospholipids often include at least one fatty acid that is kinked due to one or more double bonds. Sphingolipids tend to separate into sphingolipid-rich membrane microdomains, called lipid rafts. This has been attributed to the close packing of sphingolipids, with their fully saturated hydrocarbon tails.
  • Slide 20
  • Peripheral proteins are on the membrane surface. They are water-soluble, with mostly hydrophilic surfaces. Many peripheral proteins adhere to exposed domains of integral proteins, e.g., by ionic & H-bond interactions. They often can be dislodged by high salt concentrations, change of pH, and/or chelators that bind divalent cations. Membrane proteins peripheral integral having a lipid anchor
  • Slide 21
  • Some cytosolic proteins temporarily bind to membranes, via domains that recognize and bind to particular lipids that transiently exist in the membrane. For example: Pleckstrin homology domains (PH) bind phosphorylated derivatives of phosphatidylinositol. A PH domain has a unique sandwich structure (2 orthogonal sheets capped at one end by an amphipathic helix). Many signal proteins include PH domains, that promote their binding to the cytosolic surface of the plasma membrane, where they cooperate in signal cascades. Kinases that transfer P i to the inositol moiety of phosphatidylinositol, creating ligands for PH domains, are themselves regulated by signal pathways.
  • Slide 22
  • FYVE domains bind to a particular phosphatidylinositol derivative, phosphatidylinositol-3-phosphate. FYVE domains include specific structural motifs in which zinc ions are bound by Cys & His residues.
  • Slide 23
  • C1 domains recognize and bind to diacylglycerol, which is generated by signal-activated cleavage of a phosphorylated derivative of phosphatidylinositol. C1 domains are named for a domain in an enzyme Protein Kinase C, that is activated by diacylglycerol. C1 domains are similar in structure to FYVE domains.
  • Slide 24
  • Structural & spectroscopic data indicate that a layer of relatively immobilized lipid surrounds the transmembrane portion of an integral protein. Hydrocarbon tails of lipids at the protein-lipid interface assume conformations that allow them to fill in surface irregularities of protein domains exposed to the bilayer. Integral proteins have domains that extend into the hydrocarbon core of the membrane. Often they span the bilayer.
  • Slide 25
  • Hydrophobic domains of detergents substitute for lipids in coating hydrophobic surfaces of integral proteins. This allows the proteins to dissolve in water. Without detergents, purified integral proteins tend to aggregate, as their hydrophobic surfaces come together, to minimize contact with water. Integral proteins can be removed from membranes only by treatment with detergents, amphipathic molecules that break up the lipid bilayer.
  • Slide 26
  • Some proteins have a covalently attached lipid anchor, that inserts into the bilayer. Examples: fatty acid (myristic or palmitic acid) isoprenoid (e.g., farnesyl) GPI (glycosylphosphatidylinositol, a glycolipid). Such an anchor may allow reversible membrane association. Release may occur via: a conformational change that causes the attached