Single-pass membrane protein

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

Bitopic proteins (also known as single-pass or single-spanning proteins) are transmembrane proteins that span the lipid bilayer only one time. These proteins may constitute up to 50% of all transmembrane proteins, depending on the organism, and contribute significantly to the network of interactions between different proteins in cells, including interactions via transmembrane helices. They usually include one or several water-soluble domains situated at the different sides of biological membranes, for example in single-pass transmembrane receptors. Some of them are small and serve as regulatory or structure-stabilizing subunits in large multi-protein transmembrane complexes, such as photosystems or the respiratory chain.

Topology-based classification

Bitopic proteins are classified into 4 types, depending on their transmembrane topology and location of the transmembrane helix in the amino acid sequence of the protein. According to Uniprot:

• Type I is bitopic protein with its N-terminus on the extracellular side of the membrane and removed signal peptide;
• Type II is bitopic protein with its N-terminus on the cytoplasmic side of the membrane and the transmembrane helix located close to the N-terminus, where it works as an anchor;
• Type III is bitopic protein with its N-terminus on the extracellular side of the membrane and no signal peptide;
• Type IV is bitopic protein with its N-terminus on the cytoplasmic side of the membrane, and the transmembrane helix located close to the C-terminus, where it works as an anchor.

Hence type I proteins are anchored to the lipid membrane with a stop-transfer anchor sequence and have their N-terminal domains targeted to the ER lumen during synthesis (and the extracellular space, if mature forms are located on plasmalemma). Type II and III are anchored with a signal-anchor sequence, with type II being targeted to the ER lumen with its C-terminal domain, while type III have their N-terminal domains targeted to the ER lumen. Type IV is subdivided into IV-A, with their N-terminal domains targeted to the cytosol and IV-B, with an N-terminal domain targeted to the lumen. The implications for the division in the four types are especially manifest at the time of translocation and ER-bound translation, when the protein has to be passed through the ER membrane in a direction dependent on the type.

Databases

• Membranome database is a database of bitopic proteins from several model organisms.
• Bitopic proteins in OPM database