Membrane protein

Membrane proteins perform a variety of functions vital to the survival of organisms:[2]

• Membrane receptor proteins relay signals between the cell's internal and external environments.
• Transport proteins move molecules and ions across the membrane. They can be categorized according to the Transporter Classification database.
• Membrane enzymes may have many activities, such as oxidoreductase, transferase or hydrolase.[3]
• Cell adhesion molecules allow cells to identify each other and interact. For example, proteins involved in immune response

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.

Integral membrane proteins

Schematic representation of transmembrane proteins: 1. a single transmembrane α-helix (bitopic membrane protein) 2. a polytopic transmembrane α-helical protein 3. a polytopic transmembrane β-sheet protein
The membrane is represented in light-brown.

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. One such example of this type of protein which has not been functionally characterized yet is SMIM23. They can be classified according to their relationship with the bilayer:

• 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:
  • Helix bundle proteins, which are present in all types of biological membranes;
  • Beta barrel proteins, which are found only in outer membranes of Gram-negative bacteria, and outer membranes of mitochondria and chloroplasts.[6]
• 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

Schematic representation of the different types of interaction between monotopic membrane proteins and the cell membrane: 1. interaction by an amphipathic α-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)

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.

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.

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. 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]

• Johnson JE, Cornell RB (1999). "Amphitropic proteins: regulation by reversible membrane interactions (review)". Molecular Membrane Biology. 16 (3): 217–35. doi:10.1080/096876899294544. PMID 10503244.
• Alenghat FJ, Golan DE (2013). "Membrane protein dynamics and functional implications in mammalian cells". Current Topics in Membranes. 72: 89–120. doi:10.1016/b978-0-12-417027-8.00003-9. ISBN 9780124170278. PMC 4193470. PMID 24210428.

• Annular lipid shell
• Carrier protein
• Inner nuclear membrane proteins
• Ion channel
• Ion pump (biology)
• List of MeSH codes (D12.776)
• Receptor (biochemistry)
• Transmembrane proteins