title: Structural Basis of Diverse Homophilic Recognition by Clustered α- and β-Protocadherins.
abstract: Clustered protocadherin proteins (α-, β-, and γ-Pcdhs) provide a high level of cell-surface diversity to individual vertebrate neurons, engaging in highly specific homophilic interactions to mediate important roles in mammalian neural circuit development. How Pcdhs bind homophilically through their extracellular cadherin (EC) domains among dozens of highly similar isoforms has not been determined. Here, we report crystal structures for extracellular regions from four mouse Pcdh isoforms (α4, α7, β6, and β8), revealing a canonical head-to-tail interaction mode for homophilic trans dimers comprising primary intermolecular EC1:EC4 and EC2:EC3 interactions. A subset of trans interface residues exhibit isoform-specific conservation, suggesting roles in recognition specificity. Mutation of these residues, along with trans-interacting partner residues, altered the specificities of Pcdh interactions. Together, these data show how sequence variation among Pcdh isoforms encodes their diverse strict homophilic recognition specificities, which are required for their key roles in neural circuit assembly.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Kerry Marie
authors.initials: KM
authors.lastname: Goodman
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Rotem
authors.initials: R
authors.lastname: Rubinstein
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Chan Aye
authors.initials: CA
authors.lastname: Thu
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Bahna
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Seetha
authors.initials: S
authors.lastname: Mannepalli
authors.affiliation: Department of Systems Biology, Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA.
authors.forename: Göran
authors.initials: G
authors.lastname: Ahlsén
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Chelsea
authors.initials: C
authors.lastname: Rittenhouse
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10032, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Maniatis
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10032, USA. Electronic address: bh6@cumc.columbia.edu.
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain and Behavior Institute, Columbia University, New York, NY 10032, USA. Electronic address: shapiro@convex.hhmi.columbia.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
mesh_terms: D000595:Amino Acid Sequence / Q000502:physiology*; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D009415:Nerve Net / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms / Q000378:metabolism
chemical_list: D015820:Cadherins; D020033:Protein Isoforms