γ-Protocadherin structural diversity and functional implications

Elife. 2016 Oct 26;5:e20930. doi: 10.7554/eLife.20930.

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

Keywords: biophysics; clustered protocadherins; crystal structure; mouse; neuronal self-avoidance; neuroscience; protein diversity; protein-protein recognition; structural biology.

MeSH terms

  • Animals
  • Cadherin Related Proteins
  • Cadherins / chemistry*
  • Cadherins / metabolism*
  • Crystallography, X-Ray
  • Mice
  • Models, Molecular
  • Protein Conformation
  • Protein Isoforms / chemistry*
  • Protein Isoforms / metabolism*
  • Protein Multimerization

Substances

  • Cadherin Related Proteins
  • Cadherins
  • Gamma-protocadherins
  • Protein Isoforms