Membrane protein

Crystal structure of Potassium channel Kv1.2/2.1 Chimera. Calculated hydrocarbon boundaries of the lipid bilayer are indicated by red and blue dots.

Membrane proteins are proteins that interact with biological membranes. They are one of the common types of protein along with soluble globular proteins, fibrous proteins, and disordered proteins.^[1] They are targets of over 50% of all modern medicinal drugs.^[2] It is estimated that 20–30% of all genes in most genomes encode membrane proteins.^[3]

Function

Membrane proteins perform a variety of functions vital to the survival of organisms:^[4]

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.
Cell adhesion molecules allow cells to identify each other and interact. For example, proteins involved in immune response.

Topology

The topology of an integral membrane protein describes the number of transmembrane segments, as well as the orientation in the membrane.^[5] Membrane proteins have several different topologies:^[6]

A slightly different classification is to divide all membrane proteins to integral and amphitropic.^[7] Amphitropic proteins exist in two alternative states: a water-soluble and a lipid bilayer-bound. The amphitropic protein category includes water-soluble channel-forming polypeptide toxins, which associate irreversibly with membranes, but excludes peripheral proteins that interact with other membrane proteins rather than with lipid bilayer.

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.

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. They can be classified according to their relationship with the bilayer:

Integral polytopic proteins, also known as "transmembrane proteins," are integral membrane proteins that span across the membrane at least once. They have one of two tertiary structures:
- 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, lipid-rich cell walls of a few Gram-positive bacteria, and outer membranes of mitochondria and chloroplasts.
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)

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 or prenyl chains, or GPI (glycosylphosphatidylinositol), which may be anchored in the lipid bilayer.

Polypeptide toxins

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.

3D Structure

Increase in the number of 3D structures of membrane proteins known

The most common tertiary structures are helix bundle and beta barrel. The portion of the membrane proteins that are attached to the lipid bilayer (see annular lipid shell) are consisting of hydrophobic amino acids only. This is done so that the peptide bonds' carbonyl and amine will react with each other instead of the hydrophobic surrounding. The portion of the protein that is not touching the lipid bilayer and is protruding out of the cell membrane are usually hydrophilic amino acids.^[8]

Membrane proteins have hydrophobic surfaces, are relatively flexible and are expressed at relatively low levels. This creates difficulties in obtaining enough protein and then growing crystals. Hence, despite the significant functional importance of membrane proteins, determining atomic resolution structures for these proteins is more difficult than globular proteins.^[9] As of January 2013 less than 0.1% of protein structures determined were membrane proteins despite being 20-30% of the total proteome.^[10]

Many of the successful membrane protein structures are characterized by X-ray crystallography and are very large structures in which the interactions with the membrane mimetic environments can be anticipated to be small in comparison to those within the protein structures. The small domains are particularly sensitive to the influence of membrane mimetic environments, with potential to lead to non-native structures. However, there are many sample preparation conditions that can be chosen for crystallization and for solution NMR. All membrane protein structural biology should be subjected to careful scrutiny; through a combination of structural methodologies it should be possible to achieve an understanding of the native functional state for membrane protein structures.^[11] Coevolution information has been successfully exploited for prediction of multiple large (membrane) protein structures.^[12]^[13]^[14]

Due to this difficulty and the importance of this class of proteins methods of protein structure prediction based on hydropathy plots and the positive inside rule have been developed.^[15]^[16]