Rucete ✏ Lehninger Principles of Biochemistry In a Nutshell
11.2 Membrane Dynamics
This chapter explains how biological membranes remain flexible, dynamic, and functional through lipid movement, membrane microdomains, curvature changes, fusion events, and surface adhesion proteins.
Membranes Are Dynamic and Plastic
• A major property of biological membranes is plasticity, the ability to change shape without losing integrity or becoming leaky.
• This flexibility is possible because membrane lipids interact mainly through noncovalent forces rather than permanent covalent bonds.
• Individual lipid molecules are mobile because they are not chemically attached to one another.
• As a result, membranes can bend, fuse, bud, and reorganize while remaining continuous barriers.
Acyl Groups in Bilayers Have Different Degrees of Order
• Although the bilayer itself is stable, individual phospholipids can move extensively.
• The amount of motion depends mainly on temperature and membrane lipid composition.
• Membrane lipids can exist in two major physical states: liquid-ordered and liquid-disordered.
Liquid-Ordered State
• At lower temperatures, lipids form a gel-like liquid-ordered state.
• Polar head groups are arranged regularly.
• Fatty acyl chains are tightly packed and nearly motionless.
• Lateral and rotational movement of lipids is strongly restricted.
Liquid-Disordered State
• At higher temperatures, membranes become liquid-disordered.
• Hydrocarbon chains rotate around carbon-carbon bonds and move constantly.
• Lipids diffuse laterally in the plane of the membrane.
• Bilayer dimensions remain similar, but individual molecules gain much more mobility.
Factors Affecting Membrane Fluidity
• Long saturated fatty acids such as 16:0 and 18:0 pack tightly and favor the liquid-ordered state.
• Unsaturated fatty acids contain double-bond kinks that disrupt packing and favor the liquid-disordered state.
• Shorter fatty acid chains are more mobile than longer chains and therefore increase fluidity.
• Sterol content is another major determinant of membrane fluidity.
Effects of Cholesterol
• Cholesterol has paradoxical effects depending on surrounding lipids.
• With unsaturated phospholipids, cholesterol compacts the membrane and reduces motion.
• With long saturated lipids and sphingolipids, cholesterol prevents rigid gel formation and maintains fluidity.
• In mixed biological membranes, cholesterol often associates with sphingolipids to create liquid-ordered regions surrounded by more fluid areas.
Transbilayer Movement of Lipids Requires Catalysis
• At physiological temperature, lateral diffusion within one leaflet is rapid.
• Movement from one leaflet to the other, called flip-flop diffusion, is extremely slow without assistance.
• Flip-flop is energetically unfavorable because a polar head group must pass through the hydrophobic membrane core.
• However, some cellular processes require lipids to move between leaflets.
Examples of Required Flip-Flop
• In the endoplasmic reticulum, glycerophospholipids are synthesized on the cytosolic side.
• Sphingolipids are synthesized or modified on the lumenal side.
• Lipids must cross the bilayer to reach their correct final destination.
Lipid Translocators
• Specialized membrane proteins catalyze transbilayer movement.
• These include flippases, floppases, scramblases, and phosphatidylinositol transfer proteins.
• Like enzymes, they provide an energetically favorable pathway.
• Together with asymmetric biosynthesis, they create leaflet asymmetry in membranes.
Flippases
• Flippases move phosphatidylethanolamine (PE) and phosphatidylserine (PS) from the outer leaflet to the cytoplasmic leaflet.
• This helps maintain PE and PS mainly on the inside of plasma membranes.
• Sphingolipids and phosphatidylcholine remain enriched in the outer leaflet.
• Exposure of phosphatidylserine on the outer surface signals apoptosis and promotes engulfment by macrophages.
• ER flippases also move newly synthesized phospholipids to the lumenal leaflet.
• Flippases consume about one ATP per phospholipid moved.
• They are related to P-type ATPases.
Floppases
• Floppases move phospholipids and sterols from the cytoplasmic leaflet to the extracellular leaflet.
• They require ATP.
• They belong to the ABC transporter family.
• Different floppases specialize in transporting cholesterol, phosphatidylcholine, sphingomyelin, or phosphatidylserine.
Scramblases
• Scramblases move phospholipids in either direction down their concentration gradient.
• They do not require ATP, though some require calcium.
• Their activity randomizes lipid head-group distribution between leaflets.
• Scramblases become active during cell activation, injury, or apoptosis.
Phosphatidylinositol Transfer Proteins
• These proteins mainly transfer phosphatidylinositol lipids.
• They play important roles in membrane trafficking and lipid signaling.
Lateral Diffusion of Lipids
• Lipid molecules move laterally within the membrane by Brownian motion.
• They exchange positions with neighboring lipids.
• This randomizes membrane organization within seconds.
FRAP Technique
• Lateral movement can be measured by fluorescence recovery after photobleaching (FRAP).
• Lipids are fluorescently labeled.
• A small membrane region is bleached with a laser.
• Unbleached lipids then diffuse into the region, restoring fluorescence.
• Recovery speed indicates the diffusion rate.
• Some lipids diffuse as fast as 1 μm/s, allowing movement across a eukaryotic cell in seconds.
Single Particle Tracking and Hop Diffusion
• Single particle tracking follows individual molecules at short time scales.
• Lipids move rapidly within small local regions.
• Crossing from one region to another is less common.
• This is called hop diffusion.
• Lipids behave as though trapped in corrals separated by fences they occasionally cross.
Lateral Diffusion of Proteins
• Many membrane proteins also diffuse laterally.
• Some proteins form stable clusters or patches where molecules do not move independently.
• Example: acetylcholine receptors form dense patches at synapses.
• Other proteins are anchored to cytoskeletal structures.
Erythrocyte Example
• In red blood cells, glycophorin and the chloride-bicarbonate exchanger are tethered to spectrin.
• Spectrin is a cytoskeletal protein network beneath the membrane.
• Anchored proteins may create the fences that restrict lipid movement into compartments.
Sphingolipids and Cholesterol Form Membrane Rafts
• Lipid distribution is not uniform even within one leaflet.
• Glycosphingolipids such as cerebrosides and gangliosides form transient clusters in the outer leaflet.
• These clusters tend to exclude glycerophospholipids.
• Long saturated sphingolipid chains interact strongly with cholesterol.
• These regions become thicker, more ordered, and less fluid than surrounding phospholipid-rich membrane.
• These microdomains are called membrane rafts.
Protein Sorting in Rafts
• Proteins with shorter hydrophobic helices cannot span thicker raft bilayers well and are excluded.
• Proteins with longer hydrophobic helices preferentially partition into rafts.
• Proteins can move into and out of rafts rapidly.
• However, on short biochemical time scales, many proteins remain raft-associated.
Functional Significance of Rafts
• Rafts may occupy up to 50% of the plasma membrane surface in some cells.
• A typical raft may be about 50 nm wide.
• It may contain a few thousand sphingolipids and 10–50 proteins.
• Different rafts likely contain different subsets of proteins.
• Grouping receptors and signaling proteins increases chances of collision and signaling efficiency.
• Removing cholesterol disrupts rafts and interferes with signaling.
Caveolae
• Caveolae are specialized raft domains meaning “little caves.”
• They may represent about half of total plasma membrane area in some cells.
• Caveolae contain caveolin, an integral membrane protein.
• Caveolin has two globular domains connected by a hairpin hydrophobic region inserted into the cytoplasmic leaflet.
• Three palmitoyl groups further anchor caveolin.
• Caveolins form dimers and associate with cholesterol-rich membrane areas.
• Caveolin dimers force the membrane to curve inward, creating caveolae.
• Caveolae participate in membrane trafficking and signal transduction.
Caveolae as Surface Reservoirs
• The lipid bilayer itself is not very elastic.
• If caveolin dissociates, caveolae can flatten into the membrane.
• This adds membrane surface area.
• It allows cells to expand without bursting during osmotic or mechanical stress.
Membrane Curvature and Fusion
• Curvature changes are central to membrane budding and fusion.
• Endomembrane compartments constantly reorganize through vesicle traffic.
• Fusion is required in exocytosis, endocytosis, cell division, fertilization, and viral entry.
• Many of these processes begin with local membrane curvature.
Role of Cardiolipin
• Cardiolipin is found mainly in mitochondrial membranes and bacterial membranes.
• It is cone-shaped because its head group is small relative to four fatty acyl chains.
• It can act as a wedge that creates curvature.
• In E. coli, cardiolipin is concentrated at highly curved cell poles.
Proteins That Induce Curvature
• Some proteins are intrinsically curved and bend membranes when they bind.
• Others form curved scaffolds that stabilize spontaneous bends.
BAR Domain Proteins
• BAR domain proteins form crescent-shaped dimers.
• Their positively charged concave surface binds negatively charged membrane lipids such as PIP2 and PIP3.
• This promotes inward membrane curvature.
• Some BAR proteins also contain amphipathic helices that insert like wedges into one leaflet.
• BAR proteins may also detect existing membrane curvature.
Septins
• Septins are GTP-binding proteins that polymerize at curved membrane regions.
• Humans possess 14 septin genes.
• They participate in cell division, exocytosis, phagocytosis, and apoptosis.
• Septins contain amphipathic helices that can sense or generate curvature.
• Mutations impair vesicle trafficking and neurotransmitter release.
Membrane Fusion Requires Fusion Proteins
• Specific membrane fusion must be tightly controlled.
• Fusion proteins ensure membrane recognition.
• They bring membranes close enough to remove associated water molecules.
• They disrupt local bilayer structure.
• Outer leaflets fuse first in hemifusion.
• Then both bilayers merge into one continuous membrane.
• In regulated secretion or receptor-mediated endocytosis, fusion must occur only at the correct time.
SNARE Proteins
• SNARE proteins mediate many intracellular membrane fusion events.
• v-SNAREs are on vesicles.
• t-SNAREs are on target membranes.
• NSF regulates SNARE interactions.
• During fusion, v-SNARE and t-SNARE bind and zip together into a helical bundle with SNAP25.
• This zippering pulls two membranes together and initiates fusion.
• R-SNAREs contain a key Arg residue.
• Q-SNAREs contain a key Gln residue.
• Usually R-SNAREs function as v-SNAREs and Q-SNAREs as t-SNAREs.
Synaptic Neurotransmitter Release
• At synapses, neurotransmitter-filled vesicles fuse with the plasma membrane using SNARE proteins.
• Fusion releases neurotransmitter into the synaptic cleft.
Neurotoxins Target SNAREs
• Botulinum toxin cleaves SNARE proteins.
• It blocks neurotransmission, causing paralysis and possibly death.
• Purified botulinum toxin is also used medically and cosmetically as Botox.
• Tetanus toxin also cleaves SNARE proteins.
• It causes painful muscle rigidity and lockjaw.
Integral Proteins in Surface Adhesion and Signaling
• Several plasma membrane proteins connect cells to each other or to the extracellular matrix.
Integrins
• Integrins mediate adhesion to extracellular matrix proteins and some cells or pathogens.
• They also transmit signals in both directions across the membrane.
• Integrins are heterodimers made of α and β subunits.
• Each subunit spans the membrane once.
• Their extracellular domains bind proteins such as collagen and fibronectin.
• Many ligands contain the Arg-Gly-Asp (RGD) recognition sequence.
Cadherins
• Cadherins bind identical cadherins on neighboring cells.
• This is homophilic cell-cell adhesion.
Selectins
• Selectins bind specific polysaccharides on adjacent cells in the presence of calcium.
• They are found mainly on blood cells and endothelial cells.
• They are important in blood clotting and cell interactions in circulation.
In a Nutshell
Biological membranes are highly dynamic structures whose lipids and proteins move laterally, reorganize into rafts, bend into curved shapes, and fuse during trafficking, signaling, secretion, and cell interaction. Specialized proteins such as flippases, caveolins, BAR proteins, SNAREs, integrins, cadherins, and selectins control membrane asymmetry, curvature, fusion, adhesion, and communication.