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
Affiliations
Kerry Marie Goodman
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
Rotem Rubinstein
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States
Chan Aye Thu
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
Seetha Mannepalli
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
Fabiana Bahna
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States; Howard Hughes Medical Institute, Columbia University, New York, United States
Göran Ahlsén
Department of Systems Biology, Columbia University, New York, United States; Howard Hughes Medical Institute, Columbia University, New York, United States
Chelsea Rittenhouse
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
Tom Maniatis
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, United States
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States; Howard Hughes Medical Institute, Columbia University, New York, United States; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, United States; Department of Medicine, Columbia University, New York, United States
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States; Department of Systems Biology, Columbia University, New York, United States; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, United States
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.
