γ-Protocadherin structural diversity and functional implications

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