eLife (Oct 2016)

γ-Protocadherin structural diversity and functional implications

  • Kerry Marie Goodman,
  • Rotem Rubinstein,
  • Chan Aye Thu,
  • Seetha Mannepalli,
  • Fabiana Bahna,
  • Göran Ahlsén,
  • Chelsea Rittenhouse,
  • Tom Maniatis,
  • Barry Honig,
  • Lawrence Shapiro

DOI
https://doi.org/10.7554/eLife.20930
Journal volume & issue
Vol. 5

Abstract

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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