γ-Protocadherin structural diversity and functional implications.

Abstract

Stochastic cell-surface expression of α-, β-, and γ-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 γ-Pcdhs γA1, γA8, γB2, and γB7 revealing <i>trans</i>-homodimers, and of C-terminal ectodomain fragments from γ-Pcdhs γA4 and γB2, which depict <i>cis</i>-interacting regions in monomeric form. Together these structures span the entire γ-Pcdh ectodomain. The <i>trans</i>-dimer structures reveal determinants of γ-Pcdh isoform-specific homophilic recognition. We identified and structurally mapped <i>cis</i>-dimerization mutations to the C-terminal ectodomain structures. Biophysical studies showed that Pcdh ectodomains from γB-subfamily isoforms formed <i>cis</i> dimers, whereas γA isoforms did not, but both γA and γB isoforms could interact in <i>cis</i> with α-Pcdhs. Together, these data show how interaction specificity is distributed over all domains of the γ-Pcdh <i>trans</i> interface, and suggest that subfamily- or isoform-specific <i>cis</i>-interactions may play a role in the Pcdh-mediated neuronal self-recognition code.