title: Molecular logic of neuronal self-recognition through protocadherin domain interactions.
abstract: Self-avoidance, a process preventing interactions of axons and dendrites from the same neuron during development, is mediated in vertebrates through the stochastic single-neuron expression of clustered protocadherin protein isoforms. Extracellular cadherin (EC) domains mediate isoform-specific homophilic binding between cells, conferring cell recognition through a poorly understood mechanism. Here, we report crystal structures for the EC1-EC3 domain regions from four protocadherin isoforms representing the α, β, and γ subfamilies. All are rod shaped and monomeric in solution. Biophysical measurements, cell aggregation assays, and computational docking reveal that trans binding between cells depends on the EC1-EC4 domains, which interact in an antiparallel orientation. We also show that the EC6 domains are required for the formation of cis-dimers. Overall, our results are consistent with a model in which protocadherin cis-dimers engage in a head-to-tail interaction between EC1-EC4 domains from apposed cell surfaces, possibly forming a zipper-like protein assembly, and thus providing a size-dependent self-recognition mechanism.
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.
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.
authors.forename: Holly Noelle
authors.initials: HN
authors.lastname: Wolcott
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: Goran
authors.initials: G
authors.lastname: Ahlsen
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Maxime
authors.initials: M
authors.lastname: Chevee
authors.affiliation: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Adnan
authors.initials: A
authors.lastname: Halim
authors.affiliation: Copenhagen Center for Glycomics, Departments of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen N, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Clausen
authors.affiliation: Department of Biochemistry and Molecular Biophysics, 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. Electronic address: lss8@columbia.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Shapiro
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; Department of Medicine, Columbia University, New York, NY 10032, USA; Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10032, USA; Howard Hughes Medical Institute, Columbia University, New York, NY 10032, USA. Electronic address: bh6@columbia.edu.
authors.forename: Barry
authors.initials: B
authors.lastname: Honig
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015820:Cadherins / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009424:Nervous System Physiological Phenomena; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
chemical_list: D015820:Cadherins