tetraspanin

Tetraspanins are a family of small integral membrane proteins characterized by four transmembrane domains and two extracellular loops. In humans, the tetraspanin gene family comprises about 33 members, designated TSPAN1 through TSPAN33. Tetraspanins function as organizers of membrane microdomains, coordinating the assembly, trafficking, and signaling of multiprotein complexes at the cell surface and in endosomal compartments.

Each tetraspanin spans the membrane four times, with short cytoplasmic N- and C- termini and two extracellular loops, designated EC1 and EC2. EC2 is the larger loop and contains conserved cysteine residues that form disulfide bonds, contributing to the stability of tetraspanin interactions. The cytoplasmic tails are frequently palmitoylated, promoting association with other membrane proteins and lipid rafts.

Tetraspanins act as organizers rather than classical receptors, forming the tetraspanin web by associating with partners such as integrins, MHC class I and II molecules, and other surface receptors. Through these interactions they regulate adhesion, migration, signaling, and receptor trafficking. They participate in vesicle biology by influencing exosome biogenesis and cargo sorting, and can affect viral infection or spread by serving as cofactors for certain viruses. CD9, for instance, is essential for sperm–egg fusion in several species, while CD81 and CD63 are common exosome and endosome markers.

Dysregulation of tetraspanin networks has been implicated in cancer progression and metastasis, immune disorders, and infectious diseases. Because of their surface localization and role as organizers of signaling complexes, tetraspanins are studied as diagnostic markers and as potential targets for therapies aimed at disrupting aberrant cell interactions or signaling.

Notable members include CD9, CD63, CD81, and CD151, each with distinct expression patterns and partner protein repertoires.