1. Structural Biology and Molecular Biophysics
  2. Neuroscience
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Molecular basis of sidekick-mediated cell-cell adhesion and specificity

  1. Kerry M Goodman
  2. Masahito Yamagata
  3. Xiangshu Jin
  4. Seetha Mannepalli
  5. Phinikoula S Katsamba
  6. Göran Ahlsén
  7. Alina P Sergeeva
  8. Barry Honig  Is a corresponding author
  9. Joshua R Sanes  Is a corresponding author
  10. Lawrence Shapiro  Is a corresponding author
  1. Columbia University, United States
  2. Harvard University, United States
  3. Michigan State University, United States
Research Article
  • Cited 21
  • Views 2,487
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Cite this article as: eLife 2016;5:e19058 doi: 10.7554/eLife.19058

Abstract

Sidekick (Sdk) 1 and 2 are related immunoglobulin superfamily cell adhesion proteins required for appropriate synaptic connections between specific subtypes of retinal neurons. Sdks mediate cell-cell adhesion with homophilic specificity that underlies their neuronal targeting function. Here we report crystal structures of Sdk1 and Sdk2 ectodomain regions, revealing similar homodimers mediated by the four N-terminal immunoglobulin domains (Ig1-4), arranged in a horseshoe conformation. These Ig1-4 horseshoes interact in a novel back-to-back orientation in both homodimers through Ig1:Ig2, Ig1:Ig1 and Ig3:Ig4 interactions. Structure-guided mutagenesis results show that this canonical dimer is required for both Sdk-mediated cell aggregation (via trans interactions) and Sdk clustering in isolated cells (via cis interactions). Sdk1/Sdk2 recognition specificity is encoded across Ig1-4, with Ig1-2 conferring the majority of binding affinity and differential specificity. We suggest that competition between cis and trans interactions provides a novel mechanism to sharpen the specificity of cell-cell interactions.

Article and author information

Author details

  1. Kerry M Goodman

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

    Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8193-2931
  3. Xiangshu Jin

    Department of Chemistry, Michigan State University, East Lansing, 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. Phinikoula S Katsamba

    Department of Systems Biology, 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. Alina P Sergeeva

    Department of Systems Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Barry Honig

    Department of Biochemistry and Molecular Biophysics, 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
  9. Joshua R Sanes

    Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, United States
    For correspondence
    sanesj@mcb.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8926-8836
  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

  • Lawrence Shapiro

Howard Hughes Medical Institute

  • Xiangshu Jin
  • Phinikoula S Katsamba
  • Alina P Sergeeva
  • Barry Honig

National Institutes of Health

  • Joshua R Sanes

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

Reviewing Editor

  1. Mingjie Zhang, The Hong Kong University of Science and Technology, China

Publication history

  1. Received: June 23, 2016
  2. Accepted: September 17, 2016
  3. Accepted Manuscript published: September 19, 2016 (version 1)
  4. Version of Record published: September 30, 2016 (version 2)
  5. Version of Record updated: October 4, 2016 (version 3)

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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