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
Research Article
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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.

Data availability

All relevant data generated or analysed during this study are included in the manuscript as source data files.

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)
  4. Version of Record published: March 28, 2019 (version 2)

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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