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Membrane Structure and Dynamics. CH353 February 14, 2008. Summary. Membrane Lipids Diversity and distribution Biophysics: phase transitions and diffusion Structures Membrane Proteins Classification Structures Functions: Membrane shape Membrane fusion Cell adhesion.

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membrane structure and dynamics

Membrane Structure and Dynamics

CH353 February 14, 2008


Membrane Lipids

  • Diversity and distribution
  • Biophysics: phase transitions and diffusion
  • Structures

Membrane Proteins

  • Classification
  • Structures
  • Functions:
    • Membrane shape
    • Membrane fusion
    • Cell adhesion
general properties of biomembranes
General Properties of Biomembranes
  • Non-covalent assembly of lipid and protein – fluid mosaic
  • Lipids spontaneously form a bilayer 5–8 nm thick
    • Hydrophobic interior with hydrophillic surfaces
    • Selectively impermeable to polar molecules
    • Creates a barrier for separating aqueous environments
  • Movement of lipids and proteins
    • Rapid diffusion within each monolayer
    • Slow diffusion from one monolayer to another
  • Structure and function depends on both lipid and protein
  • Asymmetry of lipids and proteins in each monolayer
  • Electrochemical differences across membrane
diversity of lipid components
Diversity of Lipid Components

Factors determining fluidity, thickness, shape and activity of biomembrane

Type of Lipid

  • glycerolipid, sphingolipid, cholesterol

Variations in acyl or ether groups

  • length, unsaturation

Head Group Alcohol

  • choline, ethanolamine, inositol, serine, carbohydrate

>1000 different combinations of acyl and head groups per eukaryotic cell

Sprong et al. 2001, Nature Rev. Mol. Biol. 2: 504.

distribution of lipids in organelles
Distribution of Lipids in Organelles
  • Cholesterol in plasma membrane
  • Cardiolipin in inner mitochondrial
  • Sphingolipids in lysosomal
distribution of lipids in bilayer
Distribution of Lipids in Bilayer

Erythrocyte plasma membrane

  • Inside (anionic groups)
    • phosphatidylethanolamine
    • phosphatidylserine
    • phosphatidylinositols
    • phosphatidic acid
  • Outside (neutral groups)
    • phosphatidylcholine
    • sphingomyelin
  • Both
    • cholesterol
fluidity of biomembranes
Fluidity of Biomembranes
  • Pure lipids have a phase transition: gel ↔ fluid

paracrystalline↔ liquid-disordered

  • Biomembranes having mixtures of lipids exist in liquid-ordered state
  • Cell changes the composition of its lipid bilayer to maintain that state
  • Less fluid membranes have longer and more saturated acyl groups
  • cis double bonds disrupt packing
  • sterols pack with saturated acyl groups; both ordered and fluid
effect of cholesterol on membranes

Phase Diagram determined by EPR (Electron Paramagnetic Resonance)







Temperature (ºC)










Cholesterol : Lecithin

Effect of Cholesterol on Membranes

Meer et al. 2008, Nature Rev. Mol. Biol. 9: 112.

lateral movement of lipids
Lateral Movement of Lipids
  • Rapid diffusion of lipids within the monolayer
  • Motion is restricted by cell structures
    • Organelles
    • Cell-cell junctions
    • Cytoskeletal elements
  • Fluorescence microscopy of single lipid
    • Rapid diffusion within a region with jumps to other regions
lateral movement of lipids1
Lateral Movement of Lipids
  • Fluorescence Recovery After Photobleaching (FRAP) Analysis
  • Outer leaflet of membrane is labeled with probe
  • Laser bleaches a spot on labeled lipids
  • Fluorescence microscopy shows rapid lateral motion of lipids into the bleached spot on membrane
transverse movement of lipids
Transverse Movement of Lipids
  • Movement of lipids from one bilayer to another is relatively slow
  • Biological flipping of lipids is catalyzed with proteins
  • P4 ATPases
  • ATP binding cassette (ABC) transporters
movement of lipids from monolayer
Movement of Lipids from Monolayer
  • t1/2 of spontaneous transfer for various lipids
  • loss of head group alcohol ↑ transbilayer diffusion
  • loss of fatty acyl group ↑ interbilayer transfer
  • liquid-ordered domains ↓ both types of transfer
  • cholesterol shows rapid transbilayer diffusion

Hothuis & Levine 2005, Nature Rev. Mol. Biol. 6: 209.

cross sectional shapes of lipids
Cross-Sectional Shapes of Lipids
  • amphipathic molecules with a single hydrocarbon chain form micelles
    • detergents
    • fatty acids
    • lysoglycerophospholipids
  • some amphipathic molecules with two hydrocarbon chains form bilayers
    • phosphatidylcholine
  • some lipids do not form stable bilayers
    • cholesterol
    • phosphatidylethanolamine
shapes of lipids determine structures
Shapes of Lipids Determine Structures
  • Lysophosphatidylcholine (lysolecithin) – conical
    • forms micelles
  • Phosphatidylcholine (lecithin)
    • cylindrical
    • forms lipid bilayer
  • Phosphatidylethanolamine
    • inverted conical
    • forms inverse micelles

(inverted hexagonal phase)

  • Lipids with non-cylindricalcross sections may have special cellular functions

Sprong et al. 2001, Nature Rev. Mol. Biol. 2: 504.

lipids determine membrane thickness
Lipids Determine Membrane Thickness
  • Phosphatidylcholine bilayer:
    • 3.5 nm thick
  • Phosphatidylcholine + cholesterol bilayer:
    • 4.0 nm thick
  • Sphingomyelin + cholesterol bilayer:
    • 4.7 nm thick
  • Lipid rafts – local regions of thicker membrane with more sphingolipid and cholesterol

Sprong et al. 2001, Nature Rev. Mol. Biol. 2: 504.

types of membrane proteins
Types of Membrane Proteins
  • Integral Proteins
    • Covalently attached to lipid or embedded in membrane
    • Require extraction with agents that interfere with hydrophobic interactions, e.g. detergents
  • Peripheral Proteins
    • Non-covalent interactions with integral proteins or lipids
    • Can be removed using mild methods disrupting ionic interactions and H-bonds
types of integral membrane proteins
Types of Integral Membrane Proteins

Type I – one transmembrane helix, N-term outside

Type II – one transmembrane helix, C-term outside

Type III – multiple transmembrane helices on single polypeptide

Type IV – multiple transmembrane helices on separate polypeptides

Type V – proteins covalently bound to lipid

Type VI – proteins with covalently bound lipid and transmembrane helix


A type I membrane protein

  • Amino-terminal domain has polar amino acids and is glycosylated
    • 15 O-linked tetrasaccharides
    • 1 N-linked glycan
  • Transmembrane domain has hydrophobic amino acids
  • Carboxy-terminal domain has polar amino acids

A type III membrane protein

  • 7 transmembrane α-helices
  • Each helix is composed of hydrophobic amino acids
  • Loops joining helices have polar amino acids
  • A light-driven H+ pump
  • Analogous to rhodopsin

(a G protein-coupled receptor)

prediction of transmembrane helices
Prediction of Transmembrane α-Helices
  • Each amino acid is given a hydropathy index based on free energy of transfer to water
  • Hydropathy of peptides within an amino acid sequence are calculated and plotted vs residue number
  • Transmembrane peptides are ones with hydropathy > 0 for 20–25 amino acids
membrane proteins with barrel structures
Membrane Proteins with β-Barrel Structures
  • Bacterial β-barrel porins
  • Transmembrane β-sheets have alternating polar and non-polar amino acids
  • Cannot use scanning hydropathy method for predicting membrane spanning β-sheets
lipid linked membrane proteins
Lipid-Linked Membrane Proteins
  • Integral proteins can be attached to membrane by covalently bound lipid
  • Acylated
    • palmitoyl on Cys or Ser
    • N-terminal myristoyl
  • Prenylated
    • C-terminal farnesyl or geranylgeranyl group
  • GPI anchor
    • C-terminal glycosyl phosphatidylinositol
imaging membrane ultrastructure using electron microscopy
Imaging Membrane Ultrastructure Using Electron Microscopy
  • Freeze-fracture/freeze-etch scanning EM
  • Specimen rapidly frozen then fractured along plane parallel to lipid bilayers
  • Sample is then shadowed with platinum and organic material is dissolved
  • The freeze-etched metal replica is then analyzed by scanning EM

Image of thylakoid membrane

structure of membrane rafts
Structure of Membrane Rafts
  • Microdomains on surface of plasma membrane
  • Sphingolipid and cholesterol in liquid-ordered state
  • Surrounding lipid in bilayer in liquid-disordered state
  • Resistant to solubilization
  • Segregate proteins based on attached lipid (fatty acyl groups pack better)
  • Caveolin embedded in some (inward curvature)
structure of membrane caveolae
Structure of Membrane Caveolae
  • Caveolae “little caves” caused by the binding of numerous caveolins in membrane rafts
  • Both bilayers are involved in the rafts
  • May have important functions in membrane trafficking and signal transduction
cell adhesion proteins
Cell Adhesion Proteins
  • Cadherins
    • homophilic interactions
  • Immunoglobulin-like domains
    • N-CAM (homophilic)
    • I-CAM (bind integrin)
  • Selectins
    • bind carbohydrate
  • Integrins
    • Combinations of α and β
    • heterophilic interactions with various ligands
    • 2-way signal tranduction (integrin activation)
cell adhesion molecules participate in leukocyte activation and extravasation
Cell Adhesion Molecules Participate in Leukocyte Activation and Extravasation
  • Inflammation causes presentation of P-selectin and platelet activating factor
  • P-selectin interacts transiently with carbohydrate ligands on leukocytes
  • PAF activates leukocyte causing activation of integrin (inside-out signalling)
  • Integrins adhere firmly with ICAM-1 and ICAM-2 on endothelial cells
integrin heterodimeric complexes
Integrin Heterodimeric Complexes

natural combinations of integrin α and β subunits and their ligands

snare conformational cycle
SNARE Conformational Cycle
  • SNARE complexes: 4 parallel α helices each C-term in membrane
  • Ca2+ required for binding R-SNARE with Q-SNAREs (acceptor)
  • ATP needed for dissociation of SNARE complexes

Jahn & Scheller 2006, Nature Rev. Mol. Biol. 7: 631

distinct snare combinations for different membrane fusions
Distinct SNARE Combinations for Different Membrane Fusions

Jahn & Scheller 2006, Nature Rev. Mol. Biol. 7: 631