10.2 Membrane structure and function

Membrane Structure and Function

Membranes define the boundary of every cell and its internal compartments. The phospholipid bilayer forms the structural foundation, while embedded proteins and other molecules give each membrane its specific functional identity. Together, these components create a selectively permeable barrier that controls what enters and exits the cell, and they enable communication between the cell and its environment.

Two properties matter most for understanding how membranes work: fluidity (how freely lipids and proteins move within the membrane plane) and asymmetry (the different lipid compositions of the two leaflets). Both are tightly regulated and directly influence processes like signaling, transport, and cell recognition.

Membrane Structure

Phospholipid Bilayer and Fluid Mosaic Model

The membrane is built from a phospholipid bilayer: two layers of phospholipids arranged so that their hydrophilic head groups face the aqueous environment on both sides, while their hydrophobic fatty acid tails pack together in the interior. This arrangement is thermodynamically favorable because it minimizes contact between hydrophobic tails and water.

The fluid mosaic model (Singer and Nicolson, 1972) describes the membrane as a two-dimensional fluid in which phospholipids and proteins move laterally within the plane of each leaflet. "Mosaic" refers to the patchwork of different proteins and lipids distributed throughout.

• Lateral diffusion is fast: a phospholipid can travel several micrometers per second within its own leaflet.
• Transverse diffusion (flip-flop) is extremely slow without enzyme assistance because the polar head group must pass through the hydrophobic core. Specific enzymes called flippases and floppases catalyze this movement when needed.
• Proteins also move laterally, though often more slowly than lipids. Some are anchored in place by cytoskeletal attachments or by interactions with other proteins.

Cholesterol and Lipid Rafts

Cholesterol is a steroid that inserts itself between phospholipids, with its hydroxyl group near the head groups and its rigid ring system interacting with the upper portions of the fatty acid tails. Its effect on fluidity depends on temperature:

• At higher temperatures, cholesterol decreases fluidity. Its rigid rings restrict the movement of neighboring fatty acid tails, making the membrane less fluid than it would otherwise be.
• At lower temperatures, cholesterol increases fluidity. It disrupts the tight, ordered packing of saturated fatty acid tails, preventing the membrane from undergoing a gel-phase transition (essentially, it keeps the membrane from "freezing" into a rigid state).

The net result is that cholesterol acts as a fluidity buffer, keeping the membrane in a functional liquid-crystalline state across a range of temperatures.

Lipid rafts are small, dynamic membrane domains enriched in cholesterol, sphingolipids, and certain proteins (particularly GPI-anchored proteins). Because sphingolipids have longer, more saturated acyl chains, these domains pack more tightly than the surrounding membrane. Lipid rafts serve as organizing platforms for signaling cascades, membrane trafficking, and endocytosis.

Glycolipids

Glycolipids are lipids with covalently attached carbohydrate groups. They are found exclusively in the outer leaflet of the plasma membrane, with their sugar moieties extending into the extracellular space.

• They participate in cell-cell recognition, signaling, and adhesion. The carbohydrate portions act as identity markers on the cell surface.
• Cerebrosides contain a single sugar residue and are abundant in the myelin sheath of nerve cells, where they contribute to electrical insulation.
• Gangliosides contain oligosaccharide chains with one or more sialic acid residues. They are concentrated in nerve cell membranes and play roles in signal transduction.
• Glycolipids also serve as receptors exploited by pathogens. For example, cholera toxin binds the ganglioside $GM_1$, and influenza virus binds sialic acid residues on glycolipids and glycoproteins.

Membrane Properties

Membrane Fluidity and Asymmetry

Fluidity describes how freely lipids and proteins diffuse within the membrane plane. Three major factors control it:

1. Temperature: Higher temperatures increase kinetic energy and fluidity. Lower temperatures decrease it.
2. Fatty acid composition: Unsaturated fatty acids introduce kinks (from cis double bonds) that prevent tight packing, increasing fluidity. Longer and more saturated chains pack more tightly, decreasing fluidity.
3. Cholesterol content: Buffers fluidity as described above.

Membrane asymmetry refers to the distinct lipid compositions of the two leaflets:

• The outer leaflet is enriched in phosphatidylcholine (PC) and sphingomyelin (SM).
• The inner leaflet contains more phosphatidylserine (PS) and phosphatidylethanolamine (PE).

This asymmetry is actively maintained by three classes of enzymes:

• Flippases move specific phospholipids (especially PS and PE) from the outer to the inner leaflet (ATP-dependent).
• Floppases move lipids from the inner to the outer leaflet (ATP-dependent).
• Scramblases randomize lipid distribution across both leaflets (not ATP-dependent, activated during specific events like apoptosis).

The asymmetry matters functionally. For instance, PS is normally kept on the inner leaflet. When a cell undergoes apoptosis, PS is exposed on the outer surface, serving as an "eat me" signal for phagocytes.

Membrane Proteins

Membrane proteins carry out most of the membrane's specific functions. They fall into two broad categories based on how they associate with the bilayer:

Integral membrane proteins are embedded in the bilayer and can only be removed by disrupting the membrane (e.g., with detergents).

• Transmembrane proteins span the entire bilayer, either as a single alpha-helix (single-pass) or multiple alpha-helices (multi-pass). Some use beta-barrels (common in the outer membranes of bacteria and mitochondria).
• Lipid-anchored proteins are covalently attached to a lipid molecule (such as a GPI anchor or a fatty acyl group) that inserts into one leaflet.

Peripheral membrane proteins associate with the membrane surface through electrostatic interactions or hydrogen bonds with integral proteins or lipid head groups. They can be removed by changes in pH or ionic strength without disrupting the bilayer.

Membrane proteins serve diverse functions:

• Transport: Ion channels provide selective pores (e.g., $K^+$ channels); carriers undergo conformational changes to shuttle solutes (e.g., glucose transporters/GLUTs for facilitated diffusion; the $Na^+/K^+$-ATPase for active transport).
• Enzymatic activity: Some membrane proteins catalyze reactions at the membrane surface (e.g., adenylyl cyclase).
• Signal transduction: Receptors like G protein-coupled receptors (GPCRs) detect extracellular ligands and relay signals to intracellular pathways.
• Cell adhesion: Proteins like cadherins and integrins connect cells to each other or to the extracellular matrix.

The topology of a transmembrane protein (which segments are inside vs. outside the cell) is determined during its synthesis and insertion into the ER membrane. Hydrophobic stretches of amino acids (typically ~20 residues for a single alpha-helical pass) form the membrane-spanning segments, while hydrophilic regions are exposed to the aqueous environment on either side.