1. Biochemistry and Chemical Biology
  2. Neuroscience
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Intramolecular domain dynamics regulate synaptic MAGUK protein interactions

  1. Nils Rademacher  Is a corresponding author
  2. Benno Kuropka
  3. Stella-Amrei Kunde
  4. Markus C Wahl
  5. Christian Freund
  6. Sarah Althea Shoichet  Is a corresponding author
  1. Charité-Universitätsmedizin Berlin, Germany
  2. Freie Universität Berlin, Germany
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Cite this article as: eLife 2019;8:e41299 doi: 10.7554/eLife.41299

Abstract

PSD-95 MAGUK family scaffold proteins are multi-domain organisers of synaptic transmission that contain three PDZ domains followed by an SH3-GK domain tandem. This domain architecture allows coordinated assembly of protein complexes composed of neurotransmitter receptors, synaptic adhesion molecules and downstream signalling effectors. Here we show that binding of monomeric CRIPT-derived PDZ3 ligands to the third PDZ domain of PSD-95 induces functional changes in the intramolecular SH3-GK domain assembly that influence subsequent homotypic and heterotypic complex formation. We identify PSD-95 interactors that differentially bind to the SH3-GK domain tandem depending on its conformational state. Among these interactors we further establish the heterotrimeric G protein subunit Gnb5 as a PSD-95 complex partner at dendritic spines of rat hippocampal neurons. The PSD-95 GK domain binds to Gnb5 and this interaction is triggered by CRIPT-derived PDZ3 ligands binding to the third PDZ domain of PSD-95, unraveling a hierarchical binding mechanism of PSD-95 complex formation.

Article and author information

Author details

  1. Nils Rademacher

    Neuroscience Research Center (NWFZ), Charité-Universitätsmedizin Berlin, Berlin, Germany
    For correspondence
    Nils.Rademacher@charite.de
    Competing interests
    The authors declare that no competing interests exist.
  2. Benno Kuropka

    Institute of Chemistry and Biochemistry/Protein Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Stella-Amrei Kunde

    Neuroscience Research Center (NWFZ), Charité-Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Markus C Wahl

    Institute of Chemistry and Biochemisty/Structural Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Christian Freund

    Institute of Chemistry and Biochemistry/Protein Biochemistry, Freie Universität Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Sarah Althea Shoichet

    Neuroscience Research Center (NWFZ), Charité-Universitätsmedizin Berlin, Berlin, Germany
    For correspondence
    sarah.shoichet@charite.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4933-7846

Funding

Deutsche Forschungsgemeinschaft (SFB958)

  • Markus C Wahl
  • Christian Freund
  • Sarah Althea Shoichet

Deutsche Forschungsgemeinschaft (SH650/2)

  • Sarah Althea Shoichet

Deutsche Forschungsgemeinschaft (EXC 257)

  • Sarah Althea Shoichet

Deutsche Forschungsgemeinschaft (SFB665)

  • Sarah Althea Shoichet

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

Ethics

Animal experimentation: All animals used were handled in accordance with the relevant guidelines and regulations. Protocols were approved by the 'Landesamt für Gesundheit und Soziales' (LaGeSo; Regional Office for Health and Social Affairs) in Berlin and animals reported under the permit number T0280/10.

Reviewing Editor

  1. Mary B Kennedy, California Institute of Technology, United States

Publication history

  1. Received: August 21, 2018
  2. Accepted: March 12, 2019
  3. Accepted Manuscript published: March 13, 2019 (version 1)

Copyright

© 2019, Rademacher 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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