The specificity of homomeric clustering of CD81 is mediated by its δ-loop.

Tetraspanins are cell membrane-scaffolding proteins interacting with one another and a repertoire of interaction partners. Through these interactions, they form extended molecular networks as tetraspanin webs or tetraspanin-enriched microdomains. Microscopic data suggest that these networks contain tetraspanin clusters, with poor overlap between clusters formed by different tetraspanins. Here, we investigate the possibility of targeting tetraspanins CD9 or CD151 to clusters formed by the tetraspanin CD81. We find that the δ-loop from the large extracellular domain of CD81 is sufficient for targeting of CD9/CD151 to CD81 clusters. Moreover, in a pull-down assay, CD9 coprecipitates more CD81 when it carries the CD81 δ-loop. In conclusion, the information for forming homomeric CD81 clusters is encoded in the δ-loop.