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Implications for tetraspanin-enriched microdomain assembly based on structures of CD9 with EWI-F

DOI: 10.26508/lsa.202000883 DOI Help

Authors: Wout Oosterheert (Utrecht University) , Katerina T. Xenaki (Utrecht University) , Viviana Neviani (Utrecht University) , Wouter Pos (uniQure Biopharma) , Sofia Doulkeridou (Utrecht University) , Jip Manshande (Utrecht University) , Nicholas M. Pearce (Utrecht University) , Loes M. J. Kroon-batenburg (Utrecht University) , Martin Lutz (Utrecht University) , Paul M. P. Van Bergen En Henegouwen (Utrecht University) , Piet Gros (Utrecht University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Life Science Alliance , VOL 3

State: Published (Approved)
Published: September 2020
Diamond Proposal Number(s): 19800

Open Access Open Access

Abstract: Tetraspanins are eukaryotic membrane proteins that contribute to a variety of signaling processes by organizing partner-receptor molecules in the plasma membrane. How tetraspanins bind and cluster partner receptors into tetraspanin-enriched microdomains is unknown. Here, we present crystal structures of the large extracellular loop of CD9 bound to nanobodies 4C8 and 4E8 and, the cryo-EM structure of 4C8-bound CD9 in complex with its partner EWI-F. CD9–EWI-F displays a tetrameric arrangement with two central EWI-F molecules, dimerized through their ectodomains, and two CD9 molecules, one bound to each EWI-F transmembrane helix through CD9-helices h3 and h4. In the crystal structures, nanobodies 4C8 and 4E8 bind CD9 at loops C and D, which is in agreement with the 4C8 conformation in the CD9–EWI-F complex. The complex varies from nearly twofold symmetric (with the two CD9 copies nearly anti-parallel) to ca. 50° bent arrangements. This flexible arrangement of CD9–EWI-F with potential CD9 homo-dimerization at either end provides a “concatenation model” for forming short linear or circular assemblies, which may explain the occurrence of tetraspanin-enriched microdomains.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ID23-2 at ESRF