Module 2

• Topic 1


  Biological membranes: lipids and membrane proteins

  
• Eukaryotes


  • Each organelle has a unique membrane

  
• Lipids


  Membrane building blocks

  
• Lipids


  • Insoluble in water
  • Amphipatic molecules (hydrophobic tail, hydrophilic head group)

  
• Types of lipids


  • Glycerophospholipids
  • Sphingolipids
  • Steroids

  
• Functions of lipids


  • Structural functions (membrane components, protein modification)
  • Metabolic functions (energy storage)
  • Other functions (cellular signalling, enzyme cofactors, electron carriers, pigments)

  
• Effects of chain length

  • Longer chains have higher melting points and lower solubility in water
• Effects of double bonds

  • Unsaturated fats have lower melting points and less close packing
• Glycerophospholipids


  Head group, often unsaturated fatty acid tails
• Sphingolipids


  Major membrane components, derivatives of the amino alcohol sphingosine

  
• Steroids


  Mostly of eukaryotic origin, most common is cholesterol
• Similar molecules in the different kingdoms
• Different membranes vary in lipid composition

  
• Biological membranes


  • Define external boundaries of cells/intracellular compartments (eukaryotic cells)
  • Regulate traffic across this boundary
  • Functions: signal transduction, cell communication, complex reaction sequences, energy transduction
  • Special properties: flexible, self-sealing/can fuse, selectively permeable, two-dimensional
• Fluid mosaic model


  Lipid bilayer (~30-40 Å thick), lipids in constant motion (free lateral diffusion, almost no unassisted flipping), membrane proteins also diffuse laterally

  
• Lipid aggregates


  Amphipatic nature of phospholipids critical to the structure of biomembranes, hydrophobic tails aggregate to exclude water

  
• Gorter and Grendel (1925) discovered lipid bilayers

  
• Stabilisation of bilayers


  • Aggregation of hydrophobic tails due to hydrophobic effect, ionic bonds between head groups and hydrogen bonds with water, van der Waals interactions between fatty acid tails

  
• Lipid mobility in phospholipid bilayers

  • Spinning without changing location (rotation around long axis), lateral diffusion (exchange position with neighbouring molecules ~107 times/s, can diffuse several mm/s at 37°C)

  
• Phase transitions in phospholipid bilayers

  • Heat disorders interactions between fatty acid tails to change membrane from gel to fluid state
• Lipids determine membrane properties

  • Long chain fatty acids aggregate extensively for low fluidity, short chain fatty acids have less surface area for higher fluidity, unsaturated fatty acids aggregate less for higher fluidity

  
• Composition determines thickness


  • Sphingomyelin associates into thicker, more gel-like bilayer than phospholipids, cholesterol increases thickness by ordering fatty acid tails and stabilising head group interactions
• Composition and curvature


  • Curvature determined by relative size of head group to fatty acid tails (PC: large head, large tails, flat; PE: small head, large tails, curved)

  
• Some aspects of membrane function require curvature (viral budding, formation of vesicles, stability of curved structures)
• Proteins also help to stabilise curved membranes
• Leaflets differ in composition

  • Most membranes have asymmetric distribution of lipids (exoplasmic leaflet rich in sphingolipids + PC, cytosolic leaflet rich in PE/PS/PI), cholesterol relatively evenly distributed

  
• Two-faced nature of bilayers

  Cytosolic and exoplasmic faces
• How asymmetry arises


  • Lipids do not spontaneously flip between leaflets, specific enzymes catalyse translocations (e.g. sphingomyelin synthesised in exoplasmic face, glycerophospholipids synthesised in cytosolic face)

  
• Membrane microdomains


  Stable associations of sphingolipids and cholesterol: lipid rafts

  
• Membrane proteins


  Proteins located in or on the membrane bilayer, different membranes have different lipid:protein ratios

  
• Membrane protein functions


  • Transporters
  • Receptors
  • Adhesion molecules
  • Lipid synthesis
  • Energy transduction (mitochondria, chloroplasts)

  
• Types of membrane proteins

  • Integral (transmembrane, intrinsic)
  • Lipid-anchored
  • Peripheral (extrinsic)

  
• Membrane protein:membrane interaction


  • Hydrophobic interactions with lipids - bilayer shell (annulus)

  
• Membrane protein structure


  • Transmembrane alpha-helices most common, limited repertoire compared to soluble proteins
• The alpha-helix and the bilayer

  • Hydrophobic amino acid side chains interact favourably with fatty acid tails, ionic interactions with head groups, one helix enough but some have more

  
• 1. protein-coupled receptors (GPCRs)

  2. transmembrane helix receptor, associated with many diseases, target of 50% of drugs
• Beta-barrel proteins


  Antiparallel beta-barrel structure, porins
• Prediction of transmembrane regions

  • Alpha-helix: 20-25 residues, beta-strand: 7-9 residues
• Lipid-anchoring of proteins


  Water-soluble proteins can be attached to membranes by covalent linkage to fatty acids, prenyls, or GPI

  
• Proteins do not "flip-flop"