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 (native) conformation of the protein in isolation from its native environment.
The localization of proteins in membranes can be predicted reliably using hydrophobicity analyses of protein sequences, i.e. the localization of hydrophobicamino acid sequences.
Integral polytopic proteins are transmembrane proteins that span across the membrane more than once. These proteins may have different transmembrane topology.[4][5] These proteins have one of two structural architectures:
Bitopic proteins are transmembrane proteins that span across the membrane only once. Transmembrane helices from these proteins have significantly different amino acid distributions to transmembrane helices from polytopic proteins.[7]
Integral monotopic proteins are integral membrane proteins that are attached to only one side of the membrane and do not span the whole way across.
Peripheral membrane proteins
[edit]Schematic representation of the different types of interaction between monotopic membrane proteins and the cell membrane: 1. interaction by an amphipathicα-helix parallel to the membrane plane (in-plane membrane helix) 2. interaction by a hydrophobic loop 3. interaction by a covalently bound membrane lipid (lipidation) 4. electrostatic or ionic interactions with membrane lipids (e.g. through a calcium ion)
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]orprenyl chains, or GPI (glycosylphosphatidylinositol), which may be anchored in the lipid bilayer.
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]
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 polyhistidine-tag is a commonly used tag for membrane protein purification,[17] and the alternative rho1D4 tag has also been successfully used.[18][19]
^Hochuli E, Bannwarth W, Döbeli H, Gentz R, Stüber D (November 1988). "Genetic Approach to Facilitate Purification of Recombinant Proteins with a Novel Metal Chelate Adsorbent". Nature Biotechnology. 6 (11): 1321–1325. doi:10.1038/nbt1188-1321. S2CID9518666.
TransportDB - Genomics-oriented database of transporters from TIGR
Membrane PDBArchived 2020-08-03 at the Wayback Machine - Database of 3D structures of integral membrane proteins and hydrophobic peptides with an emphasis on crystallization conditions
