Classifying tetraspanins: A universal system for numbering residues and a proposal for naming structural motifs and subfamilies


All tetraspanins have four transmembrane domains (TMs). The large extracellular loop (LEL) that connects the third and fourth TMs contains multiple secondary structures together with the family's signature Cys-Cys-Gly motif. These intriguing membrane proteins are involved in diverse and incompletely understood cellular processes including cell adhesion, tissue differentiation, immune cell maturation and host-parasite interactions. Here we present a classification system that accurately describes the position of each amino acid within its primary sequence based on both sequence and topological conservation of the TMs and LEL. This builds on the numbering systems that have been used in the G protein-coupled receptor (GPCR) field for nearly three decades and which have aided the understanding of GPCR structure/activity relationships and ligand interactions. The high-resolution structures of the tetraspanins CD81, CD9, CD53 and Tspan15 were used to validate the structural relevance of our new tetraspanin classification system. Modelling of all tetraspanin LELs highlighted flexibility in LEL disulfide bonding across the family and suggests that the structural arrangement of tetraspanin LELs is more complex than previously thought. We therefore propose a new subfamily naming system that addresses this added complexity and facilitates the systematic classification of human tetraspanins, shedding light on all structural motifs within the family. We anticipate that our universal tetraspanin classification system will enable progress in defining how sequence and structure inform function.

Publication DOI:
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Additional Information: Copyright © 2023, Elsevier. This accepted manuscript version is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
Uncontrolled Keywords: Alignment,Tetraspanin,Structure,Function
Publication ISSN: 1879-2642
Last Modified: 22 Jul 2024 07:34
Date Deposited: 22 Jan 2024 14:59
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Related URLs: https://www.sci ... 1475?via%3Dihub (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2024-03
Published Online Date: 2023-12-26
Accepted Date: 2023-12-14
Submitted Date: 2023-09-21
Authors: Broadbent, Luke M
Rothnie, Alice J (ORCID Profile 0000-0002-4259-7015)
Simms, John
Bill, Roslyn M (ORCID Profile 0000-0003-1331-0852)



Version: Accepted Version

Access Restriction: Restricted to Repository staff only until 26 December 2024.

License: Creative Commons Attribution Non-commercial No Derivatives

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