Biomembrane Structure and Function
Introduction and Overview
Biomembranes are essential components of all living cells; every organism has at least one membrane. Prokaryotes typically have a single membrane; eukaryotes have multiple membranes that cover different organelles (e.g., mitochondria, endoplasmic reticulum, nucleus) in addition to the plasma membrane.
Membranes differ in lipid makeup and protein makeup, which dictates their specific functions.
The plasma membrane broadly covers the cell; organelle membranes inside cells have specialized roles.
The biomembrane is a dynamic, very fluid structure where both lipids and proteins move relative to each other.
Membrane Structure: Lipid Bilayer
The plasma membrane is a lipid bilayer: lipids on the outside and lipids on the inside with a hydrophilic (polar) head group facing water and hydrophobic (nonpolar) fatty acid tails facing inward.
Membranes are also rich in various proteins, which can span the membrane or attach to the surface, defining their functions.
The bilayer forms a fluid, continuous two-dimensional sheet that can bend, curve, and form vesicles.
The term “plasma membrane” is often used interchangeably with membrane; it is sometimes referred to as a complex fluid.
Phospholipids: Structure and Amphipathicity
Phospholipids share a basic structure built on a glycerol backbone with two fatty acid tails and a polar head group (often containing a phosphate).
Common phospholipids include phosphatidylethanolamine, phosphatidylserine, and phosphatidylcholine.
Amphipathic nature: each molecule has a hydrophilic (polar) head and hydrophobic (nonpolar) tails, enabling assembly into bilayers in aqueous environments.
Fatty acid tails typically range from about 14 to 24 carbons in length (C-atoms per tail).
Tail saturation affects packing and fluidity: one or more double bonds introduce kinks that prevent tight packing; saturated tails pack tightly and reduce fluidity.
When lipids are dispersed in water and allowed to reassemble, they tend to form a bilayer with heads facing water on both sides and tails in the interior, creating a hydrophobic core.
Some lipids can form micelles (single-layer structures) depending on their geometry; bilayers form when the molecules have roughly equal cross-sectional areas of head and tail regions.
Amphipathic lipids can self-assemble into structures such as liposomes or micelles; these are used in pharmacology to deliver drugs.
Fluid Mosaic Model and Historical Context
Early ideas envisioned membranes as rigid barriers; Overton (1895) described membranes as lipid-impregnated boundaries (lipid barrier concept).
In 1935, Daniell and Davison proposed an early membrane model with pores, which was later found to be incomplete.
In 1970, Edidin and Fry (Columbia University) demonstrated membrane fluidity with a groundbreaking experiment: they fused mouse and human cells labeled with different fluorescent dyes (mouse red, human green) and showed that membrane proteins diffused and mixed across species domains after fusion, proving membrane fluidity.
Experiment outline: label mouse cell membrane proteins with red dye and human cell membrane proteins with green dye; fuse cells; observe time-dependent mixing of red and green proteins, indicating lateral mobility.
This demonstrated that biomembranes are fluid and that proteins can migrate within the lipid bilayer.
The combination of fluidity and mosaicism led to the widely accepted Fluid Mosaic Model: membranes are fluid and proteins are mosaic-like components embedded in or attached to the lipid bilayer.
Lipids in Biomembranes: Composition and Variability
The core lipid component is the phospholipid bilayer; phospholipids constitute the major lipid component, but other lipids are present (cholesterol, sphingolipids, glycolipids).
Lipids are interspersed with a large proportion of proteins; the exact lipid-to-protein ratio varies by membrane type.
Cholesterol is a lipid that modulates membrane properties;
It has a rigid steroid ring structure with a single hydrocarbon tail and a small polar head region.
Cholesterol fits between phospholipid molecules and modulates fluidity by preventing tight packing at moderate temperatures and preventing excess fluidity at high temperatures.
Depending on the membrane, cholesterol content can be high or low; some membranes have little to no cholesterol (e.g., certain mitochondrial membranes).
Examples of lipid composition across different membranes (illustrative values from transcript):
Liver cell membrane: about 17 ext{%} cholesterol, 7 ext{%} phosphatidylethanolamine, 4 ext{%} phosphatidylserine, 24 ext{%} phosphatidylcholine.
Mitochondrial membrane: almost no cholesterol; higher proportion of phosphatidylethanolamine and phosphatidylcholine relative to liver membranes.
Prokaryotic membranes: typically lack cholesterol; common lipid composition includes a high proportion of phosphatidylethanolamine (e.g., around 70 ext{%}) and other phospholipids (~30 ext{%}).
Other lipid types:
Sphingolipids: a class of lipids with a sphingosine backbone; common in neurons and myelin; head groups may be phosphates or sugars; different from glycerophospholipids.
Glycolipids: lipids with attached sugar (glycan) groups; contribute to cell recognition and signaling; commonly found in the outer leaflet of the plasma membrane.
Cholesterol: a sterol that modulates membrane properties and interacts with phospholipids.
Lipids confer asymmetry among leaflets (outer vs inner) and contribute to membrane properties such as curvature, thickness, and local domain formation.
Membrane Asymmetry and Leaflets
Biomembranes are asymmetrical: there is an outer leaflet facing the extracellular space (or lumen) and an inner leaflet facing the cytoplasm (or mitochondrial matrix).
Lipid composition is not necessarily identical between leaflets; however, there is a general tendency for certain lipids to favor one leaflet over the other.
Phosphatidylcholine (PC) tends to be more abundant in the outer leaflet in many membranes.
Phosphatidylserine (PS) is typically enriched in the inner leaflet because it carries a negative charge, which influences electrostatics and interactions with cytosolic proteins.
PS’s negative charge contributes to membrane energetics and protein interactions; PS inner-leaflet enrichment is linked to signaling and apoptosis in some contexts.
The asymmetry is functionally important for processes like cell signaling, coagulation, and fertilization, where external leaflet composition can influence ligand binding and interactions with extracellular proteins.
Glycocalyx, Glycoproteins, and Carbohydrate Roles
Glycocalyx: a carbohydrate-rich layer on the cell exterior formed by glycoproteins and glycolipids; plays roles in protection, cell recognition, and adhesion.
Glycoproteins have glycans (carbohydrate groups) attached to specific amino acids (commonly asparagine in N-linked glycosylation or serine/threonine in O-linked glycosylation).
Functions of glycocalyx include:
Providing a protective candy-coating around cells, stabilizing the membrane, and shielding the cell.
Mediating immune cell interactions and leukocyte trafficking; lectins can bind to glycan structures, guiding cells to infection sites.
Essential roles in fertilization; sperm–egg recognition requires specific glycans on egg proteins for binding.
The external carbohydrate layer is primarily on the outer leaflet and contributes to cell–cell and cell–pathogen interactions.
Membrane Proteins: Types, Orientation, and Roles
Proteins define membrane function and can be categorized by how they associate with the bilayer:
Integral (transmembrane) proteins: span the membrane; can be single-pass (one transmembrane domain) or multipass (multiple domains) and may form channels or pores.
Beta-barrel proteins: formed by beta-strands arranged into a barrel; common in bacteria and in mitochondria/chloroplasts of eukaryotes.
Peripheral proteins: associate with the membrane surfaces, either via lipid anchors or via electrostatic interactions with other membrane components; can be anchored to inner or outer leaflets.
Lipid-anchored proteins: proteins covalently attached to lipid moieties (e.g., via a fatty acid) that anchor them to the membrane.
Amphitropic (amphitrophic) proteins: can reversibly associate with membranes depending on cellular conditions (e.g., pH, calcium, phosphorylation). They can be cytosolic and membrane-bound under different conditions.
Transmembrane proteins and orientation:
Single-pass alpha-helix: spans the bilayer once; outside and inside regions can host functional domains.
Multipass alpha-helical proteins: multiple helices crossing the bilayer can form pores or channels; most residues in the transmembrane portions are hydrophobic to fit the lipid core.
Beta-barrels: sideways beta-sheet structures forming pores; often found in bacteria; in eukaryotes, typically in mitochondria and chloroplasts.
Protein distribution across leaflets:
Some proteins are primarily associated with the outer leaflet; others with the inner leaflet; many proteins are transmembrane and span both leaflets.
The function of a given membrane protein often constrains its orientation and location within the bilayer.
Examples and mechanisms:
Glycoproteins: membrane proteins with glycans; glycosylation patterns affect folding, stability, and interactions.
Amphitrophic protein kinase C (PKC) example: cytoplasmic PKC is inactive; activation involves phosphorylation and subsequent translocation to the membrane where it becomes active; demonstrates how post-translational modifications and membrane association regulate function.
Lipid rafts (microdomains) are enriched in particular lipids (often cholesterol) and serve as organizing centers for signaling and trafficking; they provide anchors for certain proteins.
Lipid Rafts and Membrane Microdomains
Lipid rafts are small, dynamic, cholesterol- and sphingolipid-enriched membrane microdomains.
They serve as organizing centers for signaling molecules and trafficking processes (endocytosis, receptor signaling, etc.).
They can be planar or non-planar; planar rafts are flat areas, while non-planar rafts are curved or other shapes, helping to compartmentalize signaling complexes.
Membrane Dynamics: Movement and FRAP
Three main types of motion for lipids and proteins in membranes (two primary, with a third often discussed):
Lateral diffusion (very common): molecules move side-to-side within the same leaflet.
Rotation: molecules spin about their own axis within the membrane plane; keeps orientation but changes facing direction of different functional groups.
Flip-flop (transverse diffusion): a lipid head group flips from one leaflet to the other; this is energetically unfavorable and rare under normal conditions; some exceptions exist with specific enzymes or conditions.
FRAP (Fluorescence Recovery After Photobleaching) is a technique used to study mobility: label a protein with a fluorescent tag, bleach a region with a laser, and observe recovery as unbleached fluorescent proteins diffuse into the bleached area, demonstrating membrane fluidity.
The common view is that both lipids and many proteins exhibit lateral mobility; however, some proteins are anchored or restricted, leading to heterogeneous mobility across membranes.
Experimental Evidence and Implications
The 1970 Edidin–Fry experiment demonstrated membrane fluidity by showing that membrane components from two different species could mix after cell fusion, indicating lateral mobility of proteins within the membrane.
The concept of a fluid mosaic model integrates fluidity with mosaic-like distribution of proteins, lipids, and carbohydrates.
Practical and Real-World Relevance
Understanding membrane composition informs drug delivery approaches: liposomes or micelles can encapsulate drugs and utilize membrane properties to facilitate entry into cells.
Cholesterol content influences membrane rigidity and permeability; imbalances in cholesterol homeostasis relate to cardiovascular disease and metabolic disorders.
Membrane asymmetry and the glycocalyx have roles in immune recognition, fertilization, and cell signaling; disruptions can affect immunity and reproduction.
Lipid rafts are implicated in signaling pathways and membrane trafficking; their dysfunction is associated with various diseases.
Take-Home Messages
Biomembranes are fluid, dynamic, and heterogeneous structures composed of a lipid bilayer with embedded and associated proteins.
The fluid mosaic model captures how lipids move laterally and how proteins are distributed in a mosaic-like pattern across the membrane.
Lipid composition (phospholipids, cholesterol, sphingolipids, glycolipids) and leaflets’ asymmetry are essential for membrane function and cellular signaling.
Proteins define membrane function (transmembrane channels, receptors, enzymes, scaffolding), with diverse modes of association (integral, peripheral, amphitropic, lipid-anchored).
Experimental evidence (e.g., FRAP, Edidin–Fry fusion) supports membrane fluidity and lateral mobility of lipids and proteins.
Real-world implications include drug delivery, cholesterol metabolism, immune recognition, and cell signaling dynamics.
Quick Reference: Key Terms and Concepts
Lipid bilayer: fundamental structure of biomembranes with hydrophilic heads and hydrophobic tails.
Amphipathic: dual affinity for water and lipids; characteristic of phospholipids.
Fluid mosaic model: membranes are fluid, with a mosaic of proteins embedded in the lipid bilayer.
Transmembrane proteins: span entire membrane; single-pass and multipass topologies exist.
Beta-barrel proteins: beta-sheet pores; common in bacteria and in mitochondria/chloroplasts of eukaryotes.
Peripheral proteins: associated with membrane surfaces; may be anchored by lipids or protein-protein interactions.
Amphitropic (amphitrophic) proteins: reversible membrane association based on cellular conditions.
Glycocalyx: carbohydrate-rich outer coating of cells; involved in protection, signaling, and fertilization.
Lipid rafts: cholesterol- and sphingolipid-enriched microdomains that organize signaling.
Asymmetry: outer vs inner leaflet composition differs; PS is usually inner-leaflet enriched due to negative charge.
FRAP: technique to measure lateral mobility of membrane components.
Saturated vs unsaturated tails: saturation (no C=C) packs tightly; unsaturation (C=C) introduces kinks that increase fluidity.
Cholesterol: modulates membrane fluidity and order; varies in amount across membranes.
Prokaryotic vs Eukaryotic membranes: differences include cholesterol content and presence of beta-barrel proteins in certain organelles.
14-24 carbons per tail, 36-37^\circ ext{C} temperatures in typical incubations,
outer vs inner leaflets, and specific percentages like 17 ext{%} cholesterol, 7 ext{%} PE, 4 ext{%} PS, 24 ext{%} PC (illustrative values from liver membranes).