Tetraspanins: structure, dynamics, and principles of partner-protein recognition.

Tetraspanins are a large, highly conserved family of four-pass transmembrane (TM) proteins that play critical roles in a variety of essential cellular functions, including cell migration, protein trafficking, maintenance of membrane integrity, and regulation of signal transduction. Tetraspanins carry out these biological functions primarily by interacting with partner proteins. Here, we summarize significant advances that have revealed fundamental principles underpinning structure-function relationships in tetraspanins. We first review the structural features of tetraspanin ectodomains and full-length apoproteins, and then discuss how recent structural studies of tetraspanin complexes have revealed plasticity in partner-protein recognition that enables tetraspanins to bind to remarkably different protein families, viral proteins, and antibody fragments. Finally, we discuss major questions and challenges that remain in studying tetraspanin complexes.
Competing Interests: Declaration of interests A.C.K. is a cofounder and consultant for Tectonic Therapeutic and Seismic Therapeutic and for the Institute for Protein Innovation, a nonprofit research institute. S.C.B. is on the board of directors of the nonprofit Institute for Protein Innovation and the Revson Foundation, is on the scientific advisory board for and receives funding from Erasca, Inc., for work unrelated to this review, is an advisor to MPM Capital, and is a consultant for IFM, Scorpion Therapeutics, Odyssey Therapeutics, Droia Ventures, and Ayala Pharmaceuticals for unrelated projects. K.J.S. has no interests to declare.
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