1. Neuroscience
  2. Structural Biology and Molecular Biophysics

Structural organization of a major neuronal G protein regulator, the RGS7-Gβ5-R7BP complex

  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  Is a corresponding author
  8. Kirill A Martemyanov  Is a corresponding author
  1. The Scripps Research Institute, United States
https://doi.org/10.7554/eLife.42150
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

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.

Metrics

  • 2,362
    views
  • 362
    downloads
  • 18
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Categories and tags

Further reading

    1. Neuroscience

    Parabrachial CGRP neurons modulate active defensive behavior under a naturalistic threat

    Gyeong Hee Pyeon, Hyewon Cho ... Yong Sang Jo
    Research Article Updated

    Recent studies suggest that calcitonin gene-related peptide (CGRP) neurons in the parabrachial nucleus (PBN) represent aversive information and signal a general alarm to the forebrain. If CGRP neurons serve as a true general alarm, their activation would modulate both passive nad active defensive behaviors depending on the magnitude and context of the threat. However, most prior research has focused on the role of CGRP neurons in passive freezing responses, with limited exploration of their involvement in active defensive behaviors. To address this, we examined the role of CGRP neurons in active defensive behavior using a predator-like robot programmed to chase mice. Our electrophysiological results revealed that CGRP neurons encode the intensity of aversive stimuli through variations in firing durations and amplitudes. Optogenetic activation of CGRP neurons during robot chasing elevated flight responses in both conditioning and retention tests, presumably by amplifying the perception of the threat as more imminent and dangerous. In contrast, animals with inactivated CGRP neurons exhibited reduced flight responses, even when the robot was programmed to appear highly threatening during conditioning. These findings expand the understanding of CGRP neurons in the PBN as a critical alarm system, capable of dynamically regulating active defensive behaviors by amplifying threat perception, and ensuring adaptive responses to varying levels of danger.

    1. Neuroscience

    Disruption of the CRF1 receptor eliminates morphine-induced sociability deficits and firing of oxytocinergic neurons in male mice

    Alessandro Piccin, Anne-Emilie Allain ... Angelo Contarino
    Research Article

    Substance-induced social behavior deficits dramatically worsen the clinical outcome of substance use disorders; yet, the underlying mechanisms remain poorly understood. Herein, we investigated the role for the corticotropin-releasing factor receptor 1 (CRF1) in the acute sociability deficits induced by morphine and the related activity of oxytocin (OXY)- and arginine-vasopressin (AVP)-expressing neurons of the paraventricular nucleus of the hypothalamus (PVN). For this purpose, we used both the CRF1 receptor-preferring antagonist compound antalarmin and the genetic mouse model of CRF1 receptor-deficiency. Antalarmin completely abolished sociability deficits induced by morphine in male, but not in female, C57BL/6J mice. Accordingly, genetic CRF1 receptor-deficiency eliminated morphine-induced sociability deficits in male mice. Ex vivo electrophysiology studies showed that antalarmin also eliminated morphine-induced firing of PVN neurons in male, but not in female, C57BL/6J mice. Likewise, genetic CRF1 receptor-deficiency reduced morphine-induced firing of PVN neurons in a CRF1 gene expression-dependent manner. The electrophysiology results consistently mirrored the behavioral results, indicating a link between morphine-induced PVN activity and sociability deficits. Interestingly, in male mice antalarmin abolished morphine-induced firing in neurons co-expressing OXY and AVP, but not in neurons expressing only AVP. In contrast, in female mice antalarmin did not affect morphine-induced firing of neurons co-expressing OXY and AVP or only OXY, indicating a selective sex-specific role for the CRF1 receptor in opiate-induced PVN OXY activity. The present findings demonstrate a major, sex-linked, role for the CRF1 receptor in sociability deficits and related brain alterations induced by morphine, suggesting new therapeutic strategy for opiate use disorders.

    1. Evolutionary Biology
    2. Neuroscience

    Vision: The inner workings of a miniature eye

    Gregor Belušič
    Insight

    The first complete 3D reconstruction of the compound eye of a minute wasp species sheds light on the nuts and bolts of size reduction.