Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors

  1. Jordana K Thibado
  2. Jean-Yves Tano
  3. Joon Lee
  4. Leslie Salas-Estrada
  5. Davide Provasi
  6. Alexa Strauss
  7. Joao Marcelo Lamim Ribeiro
  8. Guoqing Xiang
  9. Johannes Broichhagen
  10. Marta Filizola
  11. Martin J Lohse
  12. Joshua Levitz  Is a corresponding author
  1. Weill Cornell Graduate School of Medical Sciences, United States
  2. Max Delbrück Center for Molecular Medicine, Germany
  3. Weill Cornell Medicine, United States
  4. Icahn School of Medicine at Mount Sinai, United States
  5. Forschungsinstitut für Molekulare Pharmakologie, Germany

Abstract

The metabotropic glutamate receptors (mGluRs) form a family of neuromodulatory G protein-coupled receptors that contain both a seven-helix transmembrane domain (TMD) and a large extracellular ligand-binding domain (LBD) which enables stable dimerization. While numerous studies have revealed variability across subtypes in the initial activation steps at the level of LBD dimers, an understanding of inter-TMD interaction and rearrangement remains limited. Here we use a combination of single molecule fluorescence, molecular dynamics, functional assays, and conformational sensors to reveal that distinct TMD assembly properties drive differences between mGluR subtypes. We uncover a variable region within transmembrane helix 4 (TM4) that contributes to homo- and heterodimerization in a subtype-specific manner and tunes orthosteric, allosteric and basal activation. We also confirm a critical role for a conserved inter-TM6 interface in stabilizing the active state during orthosteric or allosteric activation. Together this study shows that inter-TMD assembly and dynamic rearrangement drive mGluR function with distinct properties between subtypes.

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We have provided source data files for all relevant figures.

Article and author information

Author details

  1. Jordana K Thibado

    Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jean-Yves Tano

    Receptor Signaling Lab, Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Joon Lee

    Department of Biochemistry, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Leslie Salas-Estrada

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Davide Provasi

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2868-303X
  6. Alexa Strauss

    Tri-Institutional PhD Program in Chemical Biology, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Joao Marcelo Lamim Ribeiro

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Guoqing Xiang

    Department of Biochemistry, Weill Cornell Medicine, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Johannes Broichhagen

    Department of Chemical Biology, Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3084-6595
  10. Marta Filizola

    Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Martin J Lohse

    Receptor Signaling Lab, Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Joshua Levitz

    Department of Biochemistry, Weill Cornell Medicine, New York, United States
    For correspondence
    jtl2003@med.cornell.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8169-6323

Funding

National Institute of General Medical Sciences (R35 GM124731)

  • Joshua Levitz

National Science Foundation (GRFP)

  • Jordana K Thibado

National Institute on Drug Abuse (DA038882)

  • Marta Filizola

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

Reviewing Editor

  1. Janice L Robertson, Washington University in St Louis, United States

Version history

  1. Received: January 29, 2021
  2. Accepted: April 19, 2021
  3. Accepted Manuscript published: April 21, 2021 (version 1)
  4. Version of Record published: May 6, 2021 (version 2)

Copyright

© 2021, Thibado 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. Jordana K Thibado
  2. Jean-Yves Tano
  3. Joon Lee
  4. Leslie Salas-Estrada
  5. Davide Provasi
  6. Alexa Strauss
  7. Joao Marcelo Lamim Ribeiro
  8. Guoqing Xiang
  9. Johannes Broichhagen
  10. Marta Filizola
  11. Martin J Lohse
  12. Joshua Levitz
(2021)
Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors
eLife 10:e67027.
https://doi.org/10.7554/eLife.67027

Share this article

https://doi.org/10.7554/eLife.67027

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