4.2 Membrane proteins and their functions

Membrane Protein Structure and Function

Membrane proteins handle most of the work that the lipid bilayer can't do on its own. Because the bilayer is hydrophobic at its core, it blocks most molecules from crossing freely. Membrane proteins solve this by acting as transporters, receptors, enzymes, and anchors. Understanding their types and functions is central to understanding how cells communicate, maintain homeostasis, and organize into tissues.

Types of Membrane Proteins

There are three major categories, classified by how they associate with the lipid bilayer.

Integral membrane proteins embed directly into the lipid bilayer. They have hydrophobic regions that interact with the fatty acid tails of the phospholipids, which holds them firmly in place. Two subtypes matter here:

• Transmembrane proteins span the entire bilayer. Single-pass proteins cross the membrane once; multi-pass proteins weave back and forth across it multiple times.
• Monotopic proteins partially embed into the membrane from one side without crossing all the way through.

Peripheral membrane proteins don't embed in the bilayer. Instead, they sit on the membrane surface and attach through non-covalent interactions.

• They can bind to the polar head groups of phospholipids or to exposed regions of integral proteins via electrostatic interactions.
• Some interact with lipid tails through hydrophobic contacts.
• Because their attachment is non-covalent, they can be stripped off the membrane under certain conditions, such as high salt concentration or changes in pH.

Lipid-anchored proteins are covalently linked to lipid molecules that sit within the bilayer. The lipid acts like an anchor holding the protein at the membrane surface. Common types include:

• GPI-anchored proteins (glycosylphosphatidylinositol), found on the extracellular face
• Fatty acid-anchored proteins, attached via myristoylation or palmitoylation
• Prenyl group-anchored proteins, attached via farnesylation or geranylgeranylation

Functions of Integral Proteins

Integral proteins carry out four major categories of function: transport, enzymatic activity, signal reception, and adhesion.

Transport proteins move molecules across the membrane that otherwise couldn't pass through the hydrophobic core.

• Channel proteins form pores that allow passive diffusion of specific ions or small molecules. Aquaporins, for example, transport water, while ion channels are selective for particular ions like $Na^+$, $K^+$, $Ca^{2+}$, or $Cl^-$.
• Carrier proteins bind to their cargo and change shape to shuttle it across. They come in three varieties:
  1. Uniporters move one type of molecule down its concentration gradient (e.g., GLUT transporters for glucose).
  2. Symporters move two types of molecules in the same direction simultaneously (e.g., the sodium-glucose cotransporter, SGLT).
  3. Antiporters exchange two types of molecules, moving them in opposite directions (e.g., the $Na^+/K^+$-ATPase, which pumps 3 $Na^+$ out and 2 $K^+$ in per ATP hydrolyzed).

Membrane-bound enzymes catalyze reactions right at the membrane surface.

• Receptor tyrosine kinases phosphorylate tyrosine residues on target proteins. The insulin receptor is a classic example.
• Adenylyl cyclase converts ATP to cyclic AMP (cAMP) when activated by G proteins, amplifying signals inside the cell.

Receptor proteins detect extracellular signals (ligands) and trigger intracellular responses.

• G protein-coupled receptors (GPCRs) are seven-pass transmembrane proteins. When a ligand binds, the receptor activates an associated G protein on the cytoplasmic side. The beta-adrenergic receptor, which responds to epinephrine, is one well-studied example.
• Receptor tyrosine kinases (RTKs) work differently. Ligand binding causes two receptor molecules to dimerize, and they then phosphorylate each other (autophosphorylation). The epidermal growth factor (EGF) receptor follows this mechanism.

Adhesion molecules physically connect cells to each other or to the extracellular matrix.

• Cadherins mediate calcium-dependent cell-cell adhesion. E-cadherin, for instance, holds epithelial cells together. Without calcium, cadherins lose their adhesive function.
• Integrins bridge the extracellular matrix to the intracellular cytoskeleton. The fibronectin receptor is a key example. Integrins are unique because they signal in both directions across the membrane.

Role of Peripheral Proteins

Peripheral proteins don't cross the membrane, but they're far from passive bystanders. They serve two main roles: relaying signals and providing structural support.

In cell signaling, peripheral proteins often work as intermediaries between receptors and downstream targets.

• G proteins relay signals from GPCRs to effector proteins. For example, the $G_s$ subunit activates adenylyl cyclase after a GPCR is stimulated.
• Kinases and phosphatases regulate signaling by adding or removing phosphate groups from target proteins. Src kinase is a well-known peripheral kinase involved in growth signaling.
• Scaffold proteins like AKAP79 physically organize signaling components close together, making signal transduction faster and more efficient.

In structural support, peripheral proteins link the membrane to the cytoskeleton, which controls cell shape, membrane stability, and the ability of proteins to move within the membrane.

• Spectrin forms a meshwork beneath the membrane of red blood cells, connecting to actin filaments and giving erythrocytes their flexible, biconcave shape.
• Ankyrin acts as a bridge, attaching spectrin to integral membrane proteins.
• Dystrophin links the muscle cell membrane (sarcolemma) to the cytoskeleton. Mutations in dystrophin cause Duchenne muscular dystrophy, which illustrates how critical this structural connection is.
• Talin and vinculin connect integrins to the actin cytoskeleton at focal adhesions, the points where cells grip the extracellular matrix.

Importance of Glycoproteins

Glycoproteins are membrane proteins with short carbohydrate chains (oligosaccharides) covalently attached to them. These sugar chains almost always face the extracellular side of the membrane, contributing to the glycocalyx, the carbohydrate-rich coat on the cell surface.

Two types of glycosylation are most common:

• N-linked glycosylation attaches oligosaccharides to asparagine residues.
• O-linked glycosylation attaches oligosaccharides to serine or threonine residues.

Cell identity and recognition. The sugar chains on glycoproteins act as molecular ID tags. Blood group antigens (ABO and Rh systems) are glycoproteins that determine blood type compatibility. MHC (major histocompatibility complex) proteins are glycoproteins that present antigen fragments to immune cells, which is how your immune system distinguishes "self" from "non-self."

Host-pathogen interactions. Pathogens often exploit glycoproteins to gain entry into cells. The influenza virus, for example, binds to sialic acid residues on host cell glycoproteins. Certain bacteria use glycoproteins as docking sites too: uropathogenic E. coli binds to uroplakin Ia in the urinary tract.

Cell-cell and cell-matrix adhesion. Selectins are glycoproteins that function as calcium-dependent lectins (carbohydrate-binding proteins).

• P-selectin on activated platelets and endothelial cells mediates leukocyte rolling during inflammation, which is the first step in recruiting immune cells to an injury site.
• E-selectin appears on activated endothelial cells and also binds leukocytes.
• Neural cell adhesion molecules (NCAMs) are glycoproteins involved in neurite outgrowth and synapse formation during nervous system development.

Tissue structure. Glycoproteins contribute to the physical integrity of tissues.

• Mucins are heavily glycosylated proteins that form the protective mucus layer on epithelial surfaces. MUC1, for example, lines the gastrointestinal tract.
• Proteoglycans like aggrecan provide structural support in cartilage and help regulate signaling in the extracellular matrix. Their massive sugar chains attract water, which gives cartilage its ability to resist compression.