Schematic representation of transmembrane proteins: 1. a protein with single transmembrane α-helix (a single-pass membrane protein) (bitopic) 2. a polytopic transmembrane α-helical protein 3. a polytopic transmembrane β-sheet protein The membrane is represented in yellow.
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 II: N-terminus on the cytoplasmic side of the membrane; transmembrane helix located close to the N-terminus, where it works as an anchor[6]
Type III: N-terminus on the extracellular side of the membrane; no signal peptide[7]
Type IV: N-terminus on the cytoplasmic side of the membrane; transmembrane helix located close to the C-terminus, where it works as an anchor[8]
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. 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.
A single-pass transmembrane protein typically consists of three domains, the extracellular domain, the transmembrane domain, and the intracellular domain. The transmembrane domain is the smallest at around 25 amino acid residues and forms an alpha helix inserted into the membrane bilayer. The ECD is typically much larger than the ICD and is often globular, whereas many ICDs have relatively high disorder.[9] Some proteins in this class function as monomers, but dimerization or higher-order oligomerization is common.[9][10]
