The Structure of
Biological Membranes
Thursday 8/28 2014
Mike Mueckler
mmueckler@wustl.edu
Functions of Cellular Membranes
1. Plasma membrane acts as a selectively permeable barrier to the
environment
• Uptake of nutrients
• Waste disposal
• Maintains intracellular ionic milieu
2. Plasma membrane facilitates communication
• With the environment
• With other cells
3. Intracellular membranes allow compartmentalization and
separation of different chemical reaction pathways
• Increased efficiency through proximity
• Prevent futile cycling through separation
• Protein secretion
Composition of Animal Cell Membranes
• Hydrated, proteinaceous lipid bilayers
• By weight: 20% water, 80% solids
• Solids:
Lipid
~90%
Protein
Carbohydrate (~10%)
• Phospholipids responsible for basic membrane
bilayer structure and physical properties
• Membranes are 2-dimensional fluids into which
proteins are dissolved or embedded
The Most Common Class of Phospholipid is
Formed from a Gycerol-3-P Backbone
Saturated Fatty Acid
•Palmitate and stearate most common
•14-26 carbons
•Even # of carbons
Unsaturated Fatty Acid
Structure of Phosphoglycerides
All Membrane Lipids are Amphipathic
Figure 10-2 Molecular Biology of the Cell (© Garland Science 2008)
Phosphoglycerides are Classified by their Head Groups
Phosphatidylethanolamine
Phosphatidylcholine
Phosphatidylserine
Ether Bond at C1
Phosphatidylinositol
PS and PI bear a net negative charge
at neutral pH
Sphingolipids are the Second Major
Class of Phospholipid in Animal Cells
Sphingosine
Ceramides contain sugar
moities in ether linkage to
sphingosine
Glycolipids are Abundant in Brain Cells
Figure 10-18 Molecular Biology of the Cell (© Garland Science 2008)
Membranes are formed by
the tail to tail association
of two lipid leaflets
Exoplasmic Leaflet
Cytoplasmic Leaflet
Bilayers are Thermodynamically Stable
Structures Formed from Amphathic Lipids
(Hydrophobic)
(Hydrophilic)
Figure 10-11a Molecular Biology of the Cell (© Garland Science 2008)
Lipid Bilayer Formation is Driven by
the Hydrophobic Effect
• HE causes hydrophobic surfaces such as fatty
acyl chains to aggregate in water
• Water molecules squeeze hydrophobic
molecules into as compact a surface area as
possible in order to the minimize the free
energy state (G) of the system by maximizing
the entropy (S) or degree of disorder of the
water molecules
• DG = DH  TDS
Lipid Bilayer Formation is a
Spontaneous Process
Gently mix PL and water
Vigorous mixing
Figure 1-12 Molecular Biology of the Cell, Fifth Edition (© Garland Science 2008)
The Formation of Cell-Like
Spherical Water-Filled
Bilayers is Energetically
Favorable
Figure 10-8 Molecular Biology of the Cell (© Garland Science 2008)
Phospholipids are Mesomorphic
Figure 10-7 Molecular Biology of the Cell (© Garland Science 2008)
PhosphoLipid Movements within Bilayers
(µM/sec)
(1012-1013/sec) (108-109/sec)
Figure 10-11b Molecular Biology of the Cell (© Garland Science 2008)
Pure Phospholipid Bilayers Undergo Phase Transition
Gauche Isomer Formation
All-Trans
Below Lipid Phase Transition Temp
Above Lipid Phase Transition Temp
Phosphoglyceride Biosynthesis Occurs
at the Cytoplasmic Face of the ER
Figure 12-57 Molecular Biology of the Cell (© Garland Science 2008)
A “Scramblase” Enzyme
Catalyzes Symmetric
Growth of Both Leaflets
in the ER
Figure 12-58 Molecular Biology of the Cell (© Garland Science 2008)
The Two Plasma Membrane Leaflets
Possess Different Lipid Compositions
Enriched in PC, SM, Glycolipids
Enriched in PE, PS, PI
Figure 10-16 Molecular Biology of the Cell (© Garland Science 2008)
A “Flippase” Enzyme
promotes Lipid
Asymmetry in the
Plasma Membrane
Figure 12-58 Molecular Biology of the Cell (© Garland Science 2008)
Membrane Proteins May Selectively Interact
with Specific Lipids (Lipid Annulus or Halo)
Lipid Asymmetry Also Exists in the Plane of the Bilayer
Phospholipids are Involved in Signal Transduction
1. Activation of Lipid Kinases
PI-4,5P
Figure 10-17a Molecular Biology of the Cell (© Garland Science 2008)
PI-3,4,5P
2. Phospholipases Produce Signaling
Molecules via the Degradation of
Phospholipids
Phospholipase C Activation Produces Two
Intracellular Signaling Molecules
Diacylglycerol
PI-3,4,5P
I-3,4,5P
Figure 10-17b Molecular Biology of the Cell (© Garland Science 2008)
Amphipathic Lipids Containing Rigid Planar Rings Are
Important Components of Biological Membranes
Flexible Hydrocarbon Tail
Hydrophilic
End
How Cholesterol Integrates into a
Phospholipid Bilayer
C12
Figure 10-5 Molecular Biology of the Cell (© Garland Science 2008)
Cholesterol Biosynthesis Occurs in the Cytosol and at
the ER Membrane Through Isoprenoid Intermediates
(Rate-Limiting Step in ER)
Lipid Rafts are Microdomains Enriched in
Cholesterol and SM that may be Involved in Cell
Signaling Processes
Insoluble in Triton X-100
Figure 10-14b Molecular Biology of the Cell (© Garland Science 2008)
Electron Force Microscopic Visualization
of Lipid Rafts in Artificial Bilayers
Yellow spikes are GPI-anchored protein
Figure 10-14a Molecular Biology of the Cell (© Garland Science 2008)
3 Ways in which Lipids May be Transferred
Between Different Intracellular Compartments
Vesicle Fusion
Direct Protein-Mediated Soluble Lipid
Transfer
Binding Proteins
The 3 Basic Categories of Membrane Protein
GPI Anchor
Single-Pass
Multi-pass
b-Strands
Transmembrane
Helix
Linker
Domain
Fatty acyl
anchor
Integral
Figure 10-19 Molecular Biology of the Cell (© Garland Science 2008)
LipidAnchored
Peripheral
(can also interact
via PL headgroups)
3 Types of Lipid Anchors
Figure 10-20 Molecular Biology of the Cell (© Garland Science 2008)
Membrane Domains are “Inside-Out”
Right-Side Out Soluble Protein
Figure 3-5 Molecular Biology of the Cell (© Garland Science 2008)
Functional Characterization of
Integral Membrane Proteins
Requires Solubilization and
Subsequent Reconstitution
into a Lipid Bilayer
Figure 10-31 Molecular Biology of the Cell (© Garland Science 2008)
Detergents are Critical for the Study of Integral Membrane Proteins
(Used to denature proteins)
(Used to purify Integral
Membrane Proteins)
Detergents Exist in Two Different States in Solution
(Critical Micelle Concentration)
Figure 10-29b Molecular Biology of the Cell (© Garland Science 2008)
Detergent Solubilization of Membrane Proteins
Desirable for Purification of
Integral Membrane Proteins
Beta Sheet Secondary Structure
Polypeptide backbone is
maximally extended
(rise of 3.3 Å/residue)
H-Bond
Anti-parallel Strands
Side chains alternately
extend into opposite
sides of the sheet
b-Barrel Structure of the
OmpX Porin Protein in the
Outer Membrane of E. coli
Aromatic Side Chain
anchors
Alternating Aliphatic
Side Chains
Transmembrane a-Helices
H-Bond
1. Right-handed
2. Stability in bilayer results from
maximum hydrogen bonding of peptide
backbone
3. Usually > 20 residues in length (rise of
1.5 Å/residue)
4. Exhibit various degrees of tilt with
respect to the membrane and can bend
due to helix breaking residues
5. Mostly hydrophobic side-chains in
single-pass proteins
6. Multi-pass proteins can possess
hydrophobic, polar, or amphipathic
transmembrane helices
Transmembrane Domains Can Often be Accurately
Identified by Hydrophobicity Analysis
Figure 10-22b Molecular Biology of the Cell (© Garland Science 2008)
Bacteriorhodopsin of Halobacterium
Figure 10-32 Molecular Biology of the Cell (© Garland Science 2008)
Structure of Bacteriorhodopsin
Figure 10-33 Molecular Biology of the Cell (© Garland Science 2008)
Structure of the Glycophorin A Homodimer
Coiled-Coil
Domains in
Van Der Waals
Contact
Arg and Lys Side
Chain Anchors
23 residue transmembrane helices
Structure of the Photosynthetic Reaction Center
of Rhodopseudomonas Viridis
Figure 10-34 Molecular Biology of the Cell (© Garland Science 2008)
4 Ways that Protein Mobility is Restricted
in Biological Membranes
Intramembrane ProteinProtein Interactions
Interaction with the
cytoskeleton
Interaction with the
extracellular maxtrix
Intercellular ProteinProtein Interactions
Figure 10-39 Molecular Biology of the Cell (© Garland Science 2008)