Abstract

Signaling by the G protein Coupled Receptors (GPCRs) plays fundamental role in a vast number of essential physiological functions. Precise control of GPCR signaling requires action of Regulators of G protein Signaling (RGS) proteins that deactivate heterotrimeric G proteins. RGS proteins are elaborately regulated and comprise multiple domains and subunits, yet structural organization of these assemblies is poorly understood. Here we report a crystal structure and dynamics analyses of the multisubunit complex of RGS7, a major regulator of neuronal signaling with key roles in controlling a number of drug target GPCRs and links to neuropsychiatric disease, metabolism, and cancer. The crystal structure in combination with molecular dynamics and mass spectrometry analyses reveals unique organizational features of the complex and long-range conformational changes imposed by its constituent subunits during allosteric modulation. Notably, several intermolecular interfaces in the complex work in synergy to provide coordinated modulation of this key GPCR regulator.

Data availability

Coordinate and structure factor have been deposited in the protein data bank with accession codes 6N9G. Raw HDX data are deposited at https://doi.org/10.6084/m9.figshare.7316462.v2

The following data sets were generated

Article and author information

Author details

  1. Dipak N Patil

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Erumbi S Rangarajan

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Scott J Novick

    Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Bruce D Pascal

    Department of Molecular Medicine, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Douglas J Kojetin

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8058-6168
  6. Patrick R Griffin

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Tina Izard

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States
    For correspondence
    izard@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
  8. Kirill A Martemyanov

    Department of Neuroscience, The Scripps Research Institute, Jupiter, United States
    For correspondence
    kirill@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9925-7599

Funding

National Institute on Drug Abuse (DA036596)

  • Kirill A Martemyanov

National Eye Institute (EY018139)

  • Kirill A Martemyanov

National Institute on Drug Abuse (DA042746)

  • Kirill A Martemyanov

National Institute of General Medical Sciences (GM114420)

  • Douglas J Kojetin

National Institute of Diabetes and Digestive and Kidney Diseases (DK105825)

  • Patrick R Griffin

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

Reviewing Editor

  1. José D Faraldo-Gómez, National Heart, Lung and Blood Institute, National Institutes of Health, United States

Version history

  1. Received: September 18, 2018
  2. Accepted: December 12, 2018
  3. Accepted Manuscript published: December 12, 2018 (version 1)
  4. Version of Record published: December 28, 2018 (version 2)
  5. Version of Record updated: March 2, 2020 (version 3)

Copyright

© 2018, Patil 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. Dipak N Patil
  2. Erumbi S Rangarajan
  3. Scott J Novick
  4. Bruce D Pascal
  5. Douglas J Kojetin
  6. Patrick R Griffin
  7. Tina Izard
  8. Kirill A Martemyanov
(2018)
Structural organization of a major neuronal G protein regulator, the RGS7-Gβ5-R7BP complex
eLife 7:e42150.
https://doi.org/10.7554/eLife.42150

Share this article

https://doi.org/10.7554/eLife.42150

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