A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density

Abstract

SynGAP is a Ras/Rap GTPase-activating protein (GAP) that is a major constituent of postsynaptic densities (PSDs) from mammalian forebrain. Its α1 isoform binds to all three PDZ (PSD-95, Discs-large, ZO-1) domains of PSD-95, the principal PSD scaffold, and can occupy as many as 15% of these PDZ domains. We present evidence that synGAP-α1 regulates the composition of the PSD by restricting binding to the PDZ domains of PSD-95. We show that phosphorylation by Ca2+/calmodulin-dependent protein kinase II (CaMKII) and Polo-like kinase-2 (PLK2) decreases its affinity for the PDZ domains by several fold, which would free PDZ domains for occupancy by other proteins. Finally, we show that three critical postsynaptic signaling proteins that bind to the PDZ domains of PSD-95 are present in higher concentration in PSDs isolated from mice with a heterozygous deletion of synGAP.

Article and author information

Author details

  1. Ward G Walkup

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  2. Tara L Mastro

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  3. Leslie T Schenker

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  4. Jost Vielmetter

    Beckman Institute Protein Expression Center, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  5. Rebecca Hu

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  6. Ariella Iancu

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  7. Meera Reghunathan

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  8. Barry Dylan Bannon

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    Competing interests
    No competing interests declared.
  9. Mary B Kennedy

    Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, United States
    For correspondence
    kennedym@its.caltech.edu
    Competing interests
    Mary B Kennedy, Reviewing Editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1369-0525

Funding

National Science Foundation (2006019582)

  • Ward G Walkup

National Institutes of Health (NRSA T32 GM07616)

  • Ward G Walkup

Gordon and Betty Moore Foundation (Center for Integrative Study of Cell Regulation)

  • Mary B Kennedy

Hicks Foundation

  • Mary B Kennedy

Allen and Lenabelle Davis Foundation (Endowed Chair)

  • Mary B Kennedy

National Institutes of Health (MH095095)

  • Mary B Kennedy

The Beckman Institute (Protein Expression Center)

  • Jost Vielmetter

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (#1034-15G) of the California Institute of Technology.

Copyright

© 2016, Walkup 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. Ward G Walkup
  2. Tara L Mastro
  3. Leslie T Schenker
  4. Jost Vielmetter
  5. Rebecca Hu
  6. Ariella Iancu
  7. Meera Reghunathan
  8. Barry Dylan Bannon
  9. Mary B Kennedy
(2016)
A model for regulation by SynGAP-α1 of binding of synaptic proteins to PDZ-domain 'Slots' in the postsynaptic density
eLife 5:e16813.
https://doi.org/10.7554/eLife.16813

Share this article

https://doi.org/10.7554/eLife.16813

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