title: 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 revealingtrans-homodimers, and of C-terminal ectodomain fragments from γ-Pcdhs γA4 and γB2, which depictcis-interacting regions in monomeric form. Together these structures span the entire γ-Pcdh ectodomain. Thetrans-dimer structures reveal determinants of γ-Pcdh isoform-specific homophilic recognition. We identified and structurally mappedcis-dimerization mutations to the C-terminal ectodomain structures. Biophysical studies showed that Pcdh ectodomains from γB-subfamily isoforms formedcisdimers, whereas γA isoforms did not, but both γA and γB isoforms could interact inciswith α-Pcdhs. Together, these data show how interaction specificity is distributed over all domains of the γ-Pcdhtransinterface, and suggest that subfamily- or isoform-specificcis-interactions may play a role in the Pcdh-mediated neuronal self-recognition code.
authors: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.
authors: Kerry Marie
authors: KM
authors: Goodman
authors: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.|Department of Systems Biology, Columbia University, New York, United States.
authors: Rotem
authors: R
authors: Rubinstein
authors: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.
authors: Chan Aye
authors: CA
authors: Thu
authors: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.
authors: Seetha
authors: S
authors: Mannepalli
authors: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.|Howard Hughes Medical Institute, Columbia University, New York, United States.
authors: Fabiana
authors: F
authors: Bahna
authors: Department of Systems Biology, Columbia University, New York, United States.|Howard Hughes Medical Institute, Columbia University, New York, United States.
authors: Göran
authors: G
authors: Ahlsén
authors: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.
authors: Chelsea
authors: C
authors: Rittenhouse
authors: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States.|Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, United States.
authors: Tom
authors: T
authors: Maniatis
authors: 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.
authors: Barry
authors: 0000-0002-2480-6696
authors: B
authors: Honig
authors: 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.
authors: Lawrence
authors: 0000-0001-9943-8819
authors: L
authors: Shapiro
mesh_terms: D000818:Animals; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry* / Q000378:metabolism*; D055503:Protein Multimerization
chemical_list: D000070585:Cadherin Related Proteins; D015820:Cadherins; C464785:Gamma-protocadherins; D020033:Protein Isoforms
keywords: biophysics; clustered protocadherins; crystal structure; mouse; neuronal self-avoidance; neuroscience; protein diversity; protein-protein recognition; structural biology