1. Structural Biology and Molecular Biophysics
  2. Computational and Systems Biology
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Antiparallel protocadherin homodimers use distinct affinity- and specificity-mediating regions in cadherin repeats 1-4

  1. John M Nicoludis
  2. Bennett E Vogt
  3. Anna G Green
  4. Charlotta PI Schärfe
  5. Debora S Marks
  6. Rachelle Gaudet  Is a corresponding author
  1. Harvard University, United States
  2. Harvard Medical School, United States
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Cite this article as: eLife 2016;5:e18449 doi: 10.7554/eLife.18449

Abstract

Protocadherins (Pcdhs) are cell adhesion and signaling proteins used by neurons to develop and maintain neuronal networks, relying on trans homophilic interactions between their extracellular cadherin (EC) repeat domains. We present the structure of the antiparallel EC1-4 homodimer of human PcdhγB3, a member of the γ subfamily of clustered Pcdhs. Structure and sequence comparisons of α, β, and γ clustered Pcdh isoforms illustrate that subfamilies encode specificity in distinct ways through diversification of loop region structure and composition in EC2 and EC3, which contains isoform-specific conservation of primarily polar residues. In contrast, the EC1/EC4 interface comprises hydrophobic interactions that provide non-selective dimerization affinity. Using sequence coevolution analysis, we found evidence for a similar antiparallel EC1-4 interaction in non-clustered Pcdh families. We thus deduce that the EC1-4 antiparallel homodimer is a general interaction strategy that evolved before the divergence of these distinct protocadherin families.

Article and author information

Author details

  1. John M Nicoludis

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Bennett E Vogt

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Anna G Green

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Charlotta PI Schärfe

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Debora S Marks

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Rachelle Gaudet

    Department of Molecular and Cellular Biology, Harvard University, Cambridge, United States
    For correspondence
    gaudet@mcb.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9177-054X

Funding

National Science Foundation

  • Anna G Green

National Institutes of Health (NCRR 1S10RR028832-01)

  • Debora S Marks

National Institute of General Medical Sciences (GM106303)

  • Debora S Marks

National Defense Science and Engineering Graduate Fellowship (DGE1144152)

  • John M Nicoludis

National Institute of General Medical Sciences (P41 GM103403)

  • Rachelle Gaudet

National Institutes of Health (S10 RR029205)

  • Rachelle Gaudet

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, United States

Publication history

  1. Received: June 6, 2016
  2. Accepted: July 28, 2016
  3. Accepted Manuscript published: July 29, 2016 (version 1)
  4. Version of Record published: August 26, 2016 (version 2)

Copyright

© 2016, Nicoludis 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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