Membrane protein

Membrane proteins are a major class of proteins that either form part of a biological membrane or temporarily interact with one. They are grouped by location: integral membrane proteins are a fixed component of the cell membrane, while peripheral membrane proteins attach only temporarily. These proteins are medically significant—roughly one-third of all human proteins are membrane proteins, and they are the targets for over half of all drugs.

When a transmembrane protein is being made, its RNA includes start-transfer and stop-transfer sequences. The start-transfer sequence recruits a signal recognition particle, which pauses translation until it binds to a receptor on the membrane. A translocon channel then allows the ribosome to feed the growing polypeptide directly through the membrane. Both the start and stop sequences are later clipped off. More complex embedding pathways exist in eukaryotes and prokaryotes.

Membrane proteins carry out many essential functions. Receptor proteins relay signals between the inside and outside of a cell. Transport proteins move molecules and ions across the membrane. Membrane enzymes perform activities like oxidation-reduction, transfer, or hydrolysis. Cell adhesion molecules help cells recognize and interact with each other, such as those involved in immune responses. The location of a protein in a membrane can often be predicted by analyzing its sequence for hydrophobic regions.

Integral membrane proteins are permanently attached and can only be removed using detergents, nonpolar solvents, or denaturing agents. They are classified by how they interact with the bilayer. Integral polytopic proteins cross the membrane multiple times and come in two structural types: helix bundles, found in all biological membranes, and beta barrels, found only in the outer membranes of Gram-negative bacteria, mitochondria, and chloroplasts. Bitopic proteins cross the membrane just once, and their transmembrane helices have a different amino acid composition than those of polytopic proteins. Integral monotopic proteins attach to only one side of the membrane without crossing it.

Peripheral membrane proteins bind temporarily to the lipid bilayer or to integral proteins through hydrophobic, electrostatic, and other non-covalent interactions. They can be released by treatments like high pH or high salt. Both integral and peripheral proteins can be modified after translation by adding fatty acid, diacylglycerol, prenyl chains, or GPI anchors that embed them in the bilayer.

Polypeptide toxins, many antibacterial peptides (like colicins or hemolysins), and some proteins involved in apoptosis are sometimes treated as a separate category. These are water-soluble but can change shape dramatically, form oligomeric complexes, and bind irreversibly or reversibly to the lipid bilayer.

Membrane proteins are common across genomes. It is estimated that 20–30% of all genes in most genomes code for membrane proteins. For example, about 1,000 of the roughly 4,200 proteins in *E. coli* are thought to be membrane proteins, with 600 confirmed experimentally. In humans, current estimates suggest that 30% of the genome encodes membrane proteins.

Membrane proteins are the targets of more than half of all modern drugs. They are implicated in human diseases such as heart disease, Alzheimer’s, and cystic fibrosis.

Purifying membrane proteins has always been a major challenge. By 2008, only 150 unique membrane protein structures were known, and by 2019, only 50 human membrane proteins had had their structures solved—despite about 25% of all proteins being membrane proteins. Their hydrophobic surfaces make structural and functional studies difficult. Detergents can make them water-soluble, but this can alter their structure and function. Another approach is to engineer the protein sequence by replacing hydrophobic amino acids to improve solubility.