Common coupling map advances GPCR-G protein selectivity

  1. Alexander Sebastian Hauser
  2. Charlotte Avet
  3. Claire Normand
  4. Arturo Mancini
  5. Asuka Inoue
  6. Michel Bouvier  Is a corresponding author
  7. David E Gloriam  Is a corresponding author
  1. University of Copenhagen, Denmark
  2. University of Montreal, Canada
  3. Domain Therapeutics North America, Canada
  4. Tohoku University, Japan

Abstract

Two-thirds of human hormones and one-third of clinical drugs act on membrane receptors that couple to G proteins to achieve appropriate functional responses. While G protein transducers from literature are annotated in the Guide to Pharmacology database, two recent large-scale datasets now expand the receptor-G protein 'couplome'. However, these three datasets differ in scope and reported G protein couplings giving different coverage and conclusions on GPCR-G protein signaling. Here, we report a common coupling map uncovering novel couplings supported by both large-scale studies, the selectivity/promiscuity of GPCRs and G proteins, and how the co-coupling and co-expression of G proteins compare to the families from phylogenetic relationships. The coupling map and insights on GPCR-G protein selectivity will catalyze advances in receptor research and cellular signaling towards the exploitation of G protein signaling bias in design of safer drugs.

Data availability

All underlying data are available in Spreadsheets S1-5. The obtained common coupling map is available in the online database GproteinDb at https://gproteindb.org/signprot/couplings.

The following previously published data sets were used

Article and author information

Author details

  1. Alexander Sebastian Hauser

    Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1098-6419
  2. Charlotte Avet

    Department of Biochemistry and Molecular Medicine, University of Montreal, Montréal, Canada
    Competing interests
    No competing interests declared.
  3. Claire Normand

    Domain Therapeutics North America, Montréal, Canada
    Competing interests
    Claire Normand, was an employees of Domain Therapeutics North America during part or all of this research..
  4. Arturo Mancini

    Domain Therapeutics North America, Montréal, Canada
    Competing interests
    Arturo Mancini, was an employees of Domain Therapeutics North America during part or all of this research..
  5. Asuka Inoue

    Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
    Competing interests
    No competing interests declared.
  6. Michel Bouvier

    Department of Biochemistry and Molecular Medicine, University of Montreal, Montréal, Canada
    For correspondence
    michel.bouvier@umontreal.ca
    Competing interests
    Michel Bouvier, is the president of Domain Therapeutics scientific advisory board..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1128-0100
  7. David E Gloriam

    Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
    For correspondence
    david.gloriam@sund.ku.dk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4299-7561

Funding

Canadian Institutes of Health Research (FDN-148431)

  • Michel Bouvier

Lundbeckfonden (R218-2016-1266)

  • David E Gloriam

Lundbeckfonden (R313-2019-526)

  • David E Gloriam

Novo Nordisk Fonden (NNF18OC0031226)

  • David E Gloriam

Basis for Supporting Innovative Drug Discovery and Life Science Research (JP20am0101095)

  • Asuka Inoue

Leading Asia's Private Infrastructure Fund (JP20gm0010004)

  • Asuka Inoue

Japan Agency for Medical Research and Development

  • Asuka Inoue

Takeda Science Foundation

  • Asuka Inoue

Uehara Memorial Foundation

  • Asuka Inoue

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

Copyright

© 2022, Hauser 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

  • 5,662
    views
  • 972
    downloads
  • 96
    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. Alexander Sebastian Hauser
  2. Charlotte Avet
  3. Claire Normand
  4. Arturo Mancini
  5. Asuka Inoue
  6. Michel Bouvier
  7. David E Gloriam
(2022)
Common coupling map advances GPCR-G protein selectivity
eLife 11:e74107.
https://doi.org/10.7554/eLife.74107

Share this article

https://doi.org/10.7554/eLife.74107

Further reading

    1. Computational and Systems Biology
    George N Bendzunas, Dominic P Byrne ... Natarajan Kannan
    Research Article

    In eukaryotes, protein kinase signaling is regulated by a diverse array of post-translational modifications, including phosphorylation of Ser/Thr residues and oxidation of cysteine (Cys) residues. While regulation by activation segment phosphorylation of Ser/Thr residues is well understood, relatively little is known about how oxidation of cysteine residues modulate catalysis. In this study, we investigate redox regulation of the AMPK-related brain-selective kinases (BRSK) 1 and 2, and detail how broad catalytic activity is directly regulated through reversible oxidation and reduction of evolutionarily conserved Cys residues within the catalytic domain. We show that redox-dependent control of BRSKs is a dynamic and multilayered process involving oxidative modifications of several Cys residues, including the formation of intramolecular disulfide bonds involving a pair of Cys residues near the catalytic HRD motif and a highly conserved T-loop Cys with a BRSK-specific Cys within an unusual CPE motif at the end of the activation segment. Consistently, mutation of the CPE-Cys increases catalytic activity in vitro and drives phosphorylation of the BRSK substrate Tau in cells. Molecular modeling and molecular dynamics simulations indicate that oxidation of the CPE-Cys destabilizes a conserved salt bridge network critical for allosteric activation. The occurrence of spatially proximal Cys amino acids in diverse Ser/Thr protein kinase families suggests that disulfide-mediated control of catalytic activity may be a prevalent mechanism for regulation within the broader AMPK family.

    1. Computational and Systems Biology
    2. Genetics and Genomics
    Fangluo Chen, Dylan C Sarver ... G William Wong
    Research Article

    Obesity is a major risk factor for type 2 diabetes, dyslipidemia, cardiovascular disease, and hypertension. Intriguingly, there is a subset of metabolically healthy obese (MHO) individuals who are seemingly able to maintain a healthy metabolic profile free of metabolic syndrome. The molecular underpinnings of MHO, however, are not well understood. Here, we report that CTRP10/C1QL2-deficient mice represent a unique female model of MHO. CTRP10 modulates weight gain in a striking and sexually dimorphic manner. Female, but not male, mice lacking CTRP10 develop obesity with age on a low-fat diet while maintaining an otherwise healthy metabolic profile. When fed an obesogenic diet, female Ctrp10 knockout (KO) mice show rapid weight gain. Despite pronounced obesity, Ctrp10 KO female mice do not develop steatosis, dyslipidemia, glucose intolerance, insulin resistance, oxidative stress, or low-grade inflammation. Obesity is largely uncoupled from metabolic dysregulation in female KO mice. Multi-tissue transcriptomic analyses highlighted gene expression changes and pathways associated with insulin-sensitive obesity. Transcriptional correlation of the differentially expressed gene (DEG) orthologs in humans also shows sex differences in gene connectivity within and across metabolic tissues, underscoring the conserved sex-dependent function of CTRP10. Collectively, our findings suggest that CTRP10 negatively regulates body weight in females, and that loss of CTRP10 results in benign obesity with largely preserved insulin sensitivity and metabolic health. This female MHO mouse model is valuable for understanding sex-biased mechanisms that uncouple obesity from metabolic dysfunction.