Understanding Membranes: Properties, Composition, and Function in Medical Biochemistry, Slides of Biochemistry

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Medical Biochemistry Membranes: Bilayer Properties, Transport Lecture 71 Docsity.com Membrane function • Serve as barriers to separate contents of cell from external environment or contents of organelles form remainder of the cell • Proteins in cell membrane have many functions – transport of substances across the membrane – enzymes that catalyze biochemical reactions – receptors on exterior surface that bind external ligands (e.g., hormones, growth factors) – mediators that aid ligand-receptor complex in triggering sequence of events (second messengers that alter metabolism are produced inside the cell) Docsity.com Internal Water Is Compartmentalized • Intracellular Fluid (2/3 of total water) – rich in K+ and Mg2+, phosphate major anion – protein higher • Extracellular Fluid (1/3 of total water) – high Na+ and Ca+, chloride major anion – glucose higher Docsity.com Composition of membranes varies within and between cells • Major lipids in mammalian membranes – Phospholipids – Glycosphingolipids – Cholesterol Docsity.com • Phospholipids - two major classes 1. phosphoglycerides are more common • glycerol backbone • two fatty acids in ester linkage – usually even-numbered carbons (C16, C18) – unbranched, either saturated or unsaturated • C18 or 20:4,5,8,11,14 • phosphorylated alcohol – phosphatidic acid (1,2-diacylglycerol 3- phosphate) is simplest -- key intermediate in formation of all other phospholipids Docsity.com • Sterols – most common sterol  cholesterol • almost exclusively in plasma membrane – lesser amounts in mitochondria, Golgi, nuclear membranes – generally more abundant toward outside of plasma membrane • intercalates among phospholipids of membrane with its hydroxyl group at aqueous interface and remainder of molecule within leaflet Docsity.com Membrane lipids are amphipathic • Contain both hydrophobic and hydrophilic regions (like detergents) – polar head group – nonpolar tails • Saturated fatty acids - straight tails • Unsaturated fatty acids (generally cis) - kinked tails Docsity.com What is the effect of unsaturated fatty acids? Docsity.com Membrane lipids form bilayers • Bimolecular layer (bilayer) can also satisfy thermodynamic requirement of amphipathic molecule – only ends or edges of bilayer sheet exposed to unfavorable environment – can eliminate by folding sheet back upon itself to form enclosed vesicle with no edges. – Closed bilayer is essential property of membrane • impermeable to most water-soluble molecules Docsity.com Lipid-soluble materials • Gases (oxygen, CO2, nitrogen) – little interaction with solvents, readily diffuse through hydrophobic regions of membrane • Lipid-derived molecules (e.g., steroid hormones) – readily transverse bilayer • Organic nonelectrolyte molecules – diffusion dependent upon oil-water partition coefficients (the greater lipid solubility, the greater its diffusion rate across membrane) Docsity.com Non-lipid-soluble molecules • Proteins are also amphipathic molecules – inserted into lipid bilayer – form channels for movement of ions and small molecules – serve as transporters for larger molecules Docsity.com Membranes Are Asymmetric Structures • Irregular distribution of proteins within membrane • External location of carbohydrates attached to membrane proteins • Regional asymmetries – villous border of mucosal cells – gap junctions, tight junctions, synapses Docsity.com Membranes Are Asymmetric Structures • Phospholipid asymmetry – choline-containing phospholipids located mainly in outer leaflet • phosphatidylcholine, sphingomyelin – aminophospholipids preferentially located in inner layer • phosphatidylserine, phosphatidylethanolamine – cholesterol generally present in larger amounts on the outside Docsity.com Membranes Are Asymmetric Structures • Must be limited transverse mobility (flip-flop) – half-life of asymmetry in synthetic bilayers is several weeks – enzymes for phospholipid synthesis are located on cytoplasmic side of microsomal membranes • flippases • phospholipid exchange proteins Docsity.com Integral and peripheral proteins • e.g., ankyrin, bound to integral protein “band 3” of erythrocyte membrane – spectrin, a cytoskeletal structure within erythrocyte, bound to ankyrin • plays important role in maintenance of biconcave shape of erythrocyte Docsity.com Artificial membranes model membrane function • Mixtures of one or more phospholipids treated (e.g., sonication) to form spherical vesicles  liposomes – can control lipid content to examine effects of lipid composition on certain functions – purified membrane proteins can be incorporated into these vesicles to access factors required for function – environment can be controlled and varied (e.g., ion concentrations) – can be made to entrap compounds inside (e.g., drugs, isolated genes) for drug delivery, gene therapy Docsity.com Fluid mosaic model • Singer and Nicolson (1972) – icebergs (membrane proteins) floating in a sea of predominantly phospholipid molecules – translational diffusion - integral proteins and phospholipids can move within the plane of the membrane Docsity.com Fluid mosaic model • Fluidity significantly affects membrane functions – As membrane fluidity , so does permeability to water and other small hydrophilic molecules – Lateral mobility of integral proteins increases • If active site of integral protein resides exclusively in hydrophilic regions, changing fluidity probably has little effect on activity • If protein involved in transport, with transport components span membrane, lipid phase effects may significantly alter transport rate. • EXAMPLE: Insulin receptor - As concentration of unsaturated fatty acids in membrane increased (grow in unsaturated. fatty acid rich medium), fluidity increases, receptor binds more insulin Docsity.com Fluid mosaic model • Some protein-protein interactions within plane of membrane can restrict mobility of integral proteins Docsity.com Asymmetry of proteins and lipids maintained during membrane assembly • Fusion of a vesicle with the plasma membrane preserves the orientation of any integral proteins embedded in the vesicle bilayer Docsity.com Signal Hypothesis - Entry into ER • Blobel and Sabatini - explanation for difference between free and membrane-bound ribosomes • All ribosomes have the same structure, distinction dependent upon protein possessing signal sequence Docsity.com Synthesis of secretory proteins 1. N-terminal signal sequence is synthesized 2. Signal bound by SRP, complex docks with SRP receptor on ER membrane 3. Signal sequence binds to translocon, internal channel opens, inserted into translocon 4. Polypeptide elongates, signal sequence cleaved 5. ER chaperones prevent faulty folding, carbohydrates added to specific residues 6. Ribosomes released, recycle 7. C-terminus of protein drawn into ER lumen, translocon gate shuts, protein assumes final conformation Docsity.com