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 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 Pcdhγ ectodomain. The trans-dimer structures reveal determinants of Pcdh-γ 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.

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Author details

  1. Kerry Marie Goodman

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Rotem Rubinstein

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Chan Aye Thu

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Seetha Mannepalli

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Fabiana Bahna

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Göran Ahlsén

    Department of Systems Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Chelsea Rittenhouse

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Tom Maniatis

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Barry Honig

    Center for Computational Biology and Bioinformatics, Department of Systems Biology, Columbia University, New York, United States
    For correspondence
    bh6@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2480-6696
  10. Lawrence Shapiro

    Department of Biochemistry and Molecular Biophysics, Columbia University, New York, United States
    For correspondence
    shapiro@convex.hhmi.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9943-8819

Funding

National Institutes of Health (R01GM107571)

  • Tom Maniatis
  • Lawrence Shapiro

Howard Hughes Medical Institute (R01GM062270)

  • Fabiana Bahna
  • Barry Honig

National Science Foundation (MCB-1412472)

  • Barry Honig

Howard Hughes Medical Institute

  • Fabiana Bahna
  • Göran Ahlsén
  • Barry Honig

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. William I Weis, Stanford University Medical Center, United States

Version history

  1. Received: August 23, 2016
  2. Accepted: October 6, 2016
  3. Accepted Manuscript published: October 26, 2016 (version 1)
  4. Version of Record published: November 11, 2016 (version 2)

Copyright

© 2016, Goodman et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kerry Marie Goodman
  2. Rotem Rubinstein
  3. Chan Aye Thu
  4. Seetha Mannepalli
  5. Fabiana Bahna
  6. Göran Ahlsén
  7. Chelsea Rittenhouse
  8. Tom Maniatis
  9. Barry Honig
  10. Lawrence Shapiro
(2016)
γ-Protocadherin structural diversity and functional implications
eLife 5:e20930.
https://doi.org/10.7554/eLife.20930

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https://doi.org/10.7554/eLife.20930

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