Lipid Structures & Membrane Proteins

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University of Massachusetts Amherst
Biochemistry & Molecular Bio.
David Gross

Biochem 523 Chapter 8 Notes: 8.1 • lipids make up physical structure of membrane (lipid bilayer) • lipids are defined primarily by the absence of functional groups o insoluble in water • fatty acids are simplest lipids o long-chain carboxylic acids o most common forms in plants and animals are 16 & 18 C long o saturated fatty acids have hydrocarbon tail saturated w/ H o unsaturated fatty acids contain at least 1 double bond (in cis configuration) o in biological systems fatty acids r usually esterified o in plants & animals they’re found as triacylglycerols (triglycerides)  acyl groups of 3 F.A.’s esterified to 3 hydroxyl groups of glycerol  result of condensation rxn’s  3 F.A.’s may be same or different  don’t form bilayers, not important part of membranes  form large globules serving as storage deposits for F.A.’s that can be broken down for nrg • some lipids have polar heads o glycerophospholipids contain glycerol backbone w/ F.A. groups & a P group  these molecules are amphipathic w/ hydrophobic tail & polar or charged head  ideal for forming bilayers  can be hydrolyzed w/ phospholipases o sphingolipids also found in membranes  have phosphocholine or phosphoethanolamine heads (similar to glycerophospholipids)  basic component is sphingosine  some have head groups w/ carbohydrate groups, called glycolipids (known as cerebrosides & gangliosides) • Physiological functions of lipids o cholesterol acts as terpenoid (isoprenoid) in membrane  these are lipids composed of 5-C units w/ C skeleton o can function as waterproofing agents b/c of hydrophobicity o can function as signaling molecules (taste & smell) 8.2 • lipid bilayer is a two-dimensional array of amphipathic molecules whose tails associate w/ each other, out of contact w/ water, & whose head groups interact w/ the aqueous solvent o forms spontaneously due to hydrophobic effect o composed of glycerophospholipids & sphingolipids • The bilayer is fluid o composed of mixture of lipids, no clearly defined geometry o total thickness 30Å-40Å o hydrophobic core 25Å-30Å thick o not a static structure, it is dynamic, head groups bob around, tails constantly in motion o hydrocarbon interior of bilayer is like oily layer btwn 2 aqueous compartments o fluidity of membrane described in melting point (M.P.) – the temp. of transition from an ordered crystalline state to a fluid state  in crystalline state, acyl chains pack together  in fluid phase methylene groups of acyl chains rotate freely  M.P. depends on length of acyl chains & degree of saturation o membranes remain fluid over range of temps b/c of mixture of lipids in bilayer o cholesterol helps maintain constant membrane fluidity over range of temps.:  cholesterol’s (chol.) rigid planar rings restricts movements of nearby acyl chains, decreasing membrane fluidity  insertion of chol. btwn. lipids prevents close packing, increases fluidity o diff. areas of membranes can have diff. fluidities  membrane rafts contain tightly packed chol. & sphingolipids, nearly crystalline consistency  some proteins may associate w/ rafts • natural bilayers are asymmetric o sphingolipids occur almost exclusively in outer membrane of bilayer o phosphatidylcholine also usually found in outer layer o phosphatidylserine usually found in inner layer o asymmetry a consequence of orientation of lipid-synthesizing enzymes in E.R. & Golgi o asymmetry preserved by extremely slow rate of transverse diffusion (flip- flopping)  thermodynamically unfavorable b/c polar head passing through hydrophobic interior o translocases (flippases) move lipids btwn leaflets o lateral diffusion is rapid for lipids 7  lateral movement occurs for each lipid as often as 10 times per second 8.3 Membrane Proteins • membranes about 50% protein by weight o some bacteria membranes as much as 75% protein • integral (intrinsic) membrane proteins (IMP) have portion fully buried in lipid bilayer o contrasted to peripheral & extrinsic membrane proteins, loosely associated w/ membrane via interactions w/ lipid head groups o most IMP completely span lipid bilayer, exposed to interior & exterior • popypep chains can cross bilayer w/ fully hydrophobic -helix, can mingle w/ acyl chains o needs @ least 20A.A. to span interior o usually rich in hydrophobicA.A.’s like Ile, Leu, Val, & Phe o polar A.A.’s occur when -helix approaches polar head, Trp, Tyr,Asn, & Gln o highly polar A.A.’s, Asp, Glu, Lys, &Arg, mark exposure to solvent o many IMP’s contain several membrane-spanning -helices bundled together • transmembrane β-sheets form a barrel o smallest possible barrel contains 8 strands o exterior surface includes 22Å wide band, hydrophobic side chains o flanked on each side by aromatic side chains, polar & form interface w/ lipid head groups o larger barrels (up to 22 bands) contain water-filled passageway allowing molecule transport • lipid-linked proteins (LLP) are anchored to membrane by covalently attached lipid group o a few contain membrane spanning polypep sequences 8.4 The Fluid Mosaic Model • certain lipids appear to associate specifically w/ certain proteins • lateral movement of proteins is possible o key feature of fluid mosaic model o membrane proteins like icebergs float in a lipid sea • some proteins are immobile b/c they attach to cytoskeleton • most LLP face cell interior Chapter 9 Notes: Membrane Transport • all animal cells maintain intracellular ion concentrations that differ from those outside the cell • the plasma membrane prevents their diffusion 9.1 The Thermodynamics of Membrane Transport • inside of cell more negatively charged than outside o generates a voltage across membrane, membrane potential ( ∆φ ) ∆φ= FT ln [ion]¿ • in simplest case ZF [ion]out o R = gas constant o T = temperature (K) o Z = net charge per ion o F = Faraday constant o units = volts • ion movements alter membrane potential o most animal cells have membrane potential of -70mV o in a nerve:  nerve stimulated, Na+ channels open, sodium moves in w/ gradient  membrane potential becomes more positive (up to +50mV)  this is called action potential  triggers opening of nearby voltage gated K+ channels, K+ diffuses out of cell  restores membrane potential to -70mV  also stimulates opening of Na+ channels farther along axon, action potential travels down axon o action potentials propagate very rapidly b/c of myelin sheath  several layers of membrane coiled around axon  rich in sphingomyelins, contains little protein  prevents ion movement except @ nodes between myelinated segments of axon  action potential jumps from node to node, 20x faster than unwrapped axon • transporters mediate transmembrane ion movement o passive transporters provide a means for ions to move down the concentration gradient  thermodynamically favorable o the free nrg change for the transmembrane movement of a substance from outside to in: [X] ¿  ∆G=RTln [X] out  process is spontaneous when X moves from high to low concentration o for ions, membrane potential must be added: ∆G=RTln [X] ¿ +ZF∆φ  [X]out o the protein that initially established the ion gradient of the cells is an active transporter  requires free nrg ofATP to move the ions 9.2 Passive Transport • Porins are β barrel proteins o porins are trimers where each subunit forms 16 – 18 stranded membrane-spanning β barrel  has a water filled core lined w/ hydrophilic side chains  forms transmembrane passageway for molecules w/ molec. mass up to 1000 D o porins can show solute selectivity depending on geometry of barrel interior & nature of side chains projecting into it o porins are always open and solute can travel through in either direction • ion channels are highly selective o usually multimers w/ identical subunits composed of membrane spanning - helices o K+ ion channel well known  tetrameric protein w/ each subunit composed of 3 helices • 1 forms wall of transmembrane pore • 1 faces hydrophobic membrane interior • 1 on extracellular side of protein  10,000 X more permeable to K+ than Na+  high selectivity b/c of geometry, protein folds to accommodate only K+  K+ channels in neurons is larger, 6 subunits • gated channels undergo conformational changes o K+ channels are voltage gated in neurons, opens in response to depolarization  intracellular helices move enough to open pore o can also be inactivated when N-terminal is repositioned to block cytoplasmic opening  happens right after channel opens, doesn’t allow channel to open right away o in bacterial mechanosensitive channels, -helices slide past each other • aquaporins are water-specific pores o water was thought to diffuse by osmosis through the membrane o expressed @ high levels where fluid transport is important, kidneys, salivary glands o extremely specific for water o most defined aquaporin is aquaporin 1 (AQP1)  homotetramer w/ carb chains on extracellular surface  subunits consist of 6 membrane spanning helices, & 2 within bilayer  each subunit contains a pore for water, dimensions restrict molecules  pores lined w/ hydrophobic res. exceptAsn side chains • Asn forms H-bonds w/ water passing by, prevents any protons from coming through • some transport proteins alternate between conformations o glucose transporter has glucose binding site that alternately faces exterior and interior  when glucose binds, induces conformational change to other state o they are all transmembrane proteins that alternate between conformations in order to bind and release ligand on opposite sides of the membrane o like enzymes:  accelerate rate of crossing  can be saturated by high substrate concentrations  susceptible to competitive & other inhibition types o more selective than porins & ion channels o are classified by how they operate  uniporter moves a single substance at a time  symporter transports two different substances across membrane  antiporter moves two different substance in opposite
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