?-Protocadherin structural diversity and functional implications.

ABSTRACT: Stochastic cell-surface expression of ?-, ?-, and ?-clustered protocadherins (Pcdhs) provides vertebrate neurons with single-cell identities that underlie neuronal self-recognition. Here we report crystal structures of ectodomain fragments comprising cell-cell recognition regions of mouse ?-Pcdhs ?A1, ?A8, ?B2, and ?B7 revealing trans-homodimers, and of C-terminal ectodomain fragments from ?-Pcdhs ?A4 and ?B2, which depict cis-interacting regions in monomeric form. Together these structures span the entire ?-Pcdh ectodomain. The trans-dimer structures reveal determinants of ?-Pcdh isoform-specific homophilic recognition. We identified and structurally mapped cis-dimerization mutations to the C-terminal ectodomain structures. Biophysical studies showed that Pcdh ectodomains from ?B-subfamily isoforms formed cis dimers, whereas ?A isoforms did not, but both ?A and ?B isoforms could interact in cis with ?-Pcdhs. Together, these data show how interaction specificity is distributed over all domains of the ?-Pcdh trans interface, and suggest that subfamily- or isoform-specific cis-interactions may play a role in the Pcdh-mediated neuronal self-recognition code.

SUBMITTER: Goodman KM 

PROVIDER: S-EPMC5106212 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature