Tetraspanin CD82 reduces the formation of CADM1 oligomers

Abstract

CD82 is a member of the tetraspanin protein superfamily and known as a metastasis suppressor. We identified cell adhesion molecule 1 (CADM1) as an interaction partner of CD82. CADM1 mediates cell adhesion by forming cis and trans oligomers that connect membranes. We show that CD82 reduces the formation of CADM1 oligomers when solubilized by detergent, on liposomes and in cellulo using Jurkat T-cells. Our data is consistent with a 1:1 complex of CD82 and CADM1 in cis that leaves the CADM1 trans-interaction site accessible. Cryo-electron microscopy of the CD82:CADM1 heterodimer suggests an interaction site between the large-extracellular loop of CD82 and an Ig-like domain of CADM1. Consistently, liposomes coupled with CADM1 ectodomain show reduced clustering when reconstituted with CD82. We hypothesize that CD82 may affect spacing of the transmembrane helices of CADM1, possibly by interacting with the extracellular Ig-like domains and hence disrupting CADM1 oligomerization between membranes.