Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integral membrane proteins are a permanent part of a cell membrane and can either penetrate the membrane (transmembrane) or associate with one or the other side of a membrane (integral monotopic). Peripheral membrane proteins are transiently associated with the cell membrane.
Membrane proteins are common, and medically important—about a third of all human proteins are membrane proteins, and these are targets for more than half of all drugs.[1] Nonetheless, compared to other classes of proteins, determining membrane protein structures remains a challenge in large part due to the difficulty in establishing experimental conditions that can preserve the correct conformation of the protein in isolation from its native environment.
Membrane proteins perform a variety of functions vital to the survival of organisms:[2]
The localization of proteins in membranes can be predicted reliably using hydrophobicity analyses of protein sequences, i.e. the localization of hydrophobic amino acid sequences.
Main articles: Integral membrane protein and Transmembrane protein |
Integral membrane proteins are permanently attached to the membrane. Such proteins can be separated from the biological membranes only using detergents, nonpolar solvents, or sometimes denaturing agents.[citation needed] They can be classified according to their relationship with the bilayer:
Main article: Peripheral membrane protein |
Peripheral membrane proteins are temporarily attached either to the lipid bilayer or to integral proteins by a combination of hydrophobic, electrostatic, and other non-covalent interactions. Peripheral proteins dissociate following treatment with a polar reagent, such as a solution with an elevated pH or high salt concentrations.[citation needed]
Integral and peripheral proteins may be post-translationally modified, with added fatty acid, diacylglycerol[8] or prenyl chains, or GPI (glycosylphosphatidylinositol), which may be anchored in the lipid bilayer.
Main article: Pore-forming toxin |
Polypeptide toxins and many antibacterial peptides, such as colicins or hemolysins, and certain proteins involved in apoptosis, are sometimes considered a separate category. These proteins are water-soluble but can aggregate and associate irreversibly with the lipid bilayer and become reversibly or irreversibly membrane-associated.[citation needed]
Membrane proteins, like soluble globular proteins, fibrous proteins, and disordered proteins, are common.[9] It is estimated that 20–30% of all genes in most genomes encode for membrane proteins.[10][11] For instance, about 1000 of the ~4200 proteins of E. coli are thought to be membrane proteins, 600 of which have been experimentally verified to be membrane resident.[12] In humans, current thinking suggests that fully 30% of the genome encodes membrane proteins.[13]
Membrane proteins are the targets of over 50% of all modern medicinal drugs.[1] Among the human diseases in which membrane proteins have been implicated are heart disease, Alzheimer's and cystic fibrosis.[13]
Although membrane proteins play an important role in all organisms, their purification has historically, and continues to be, a huge challenge for protein scientists. In 2008, 150 unique structures of membrane proteins were available,[14] and by 2019 only 50 human membrane proteins had had their structures elucidated.[13] In contrast, approximately 25% of all proteins are membrane proteins.[15] Their hydrophobic surfaces make structural and especially functional characterization difficult.[13][16] Detergents can be used to render membrane proteins water-soluble, but these can also alter protein structure and function.[13] Making membrane proteins water-soluble can also be achieved through engineering the protein sequence, replacing selected hydrophobic amino acids with hydrophilic ones, taking great care to maintain secondary structure while revising overall charge.[13]
Affinity chromatography is one of the best solutions for purification of membrane proteins. The activity of membrane proteins decreases very fast in contrast to other proteins.[citation needed] So, affinity chromatography provides a fast and specific purification of membrane proteins. The polyhistidine-tag is a commonly used tag for membrane protein purification,[17] and the alternative rho1D4 tag has also been successfully used.[18][19]