Rules and mechanisms governing G protein coupling selectivity of GPCRs

Ikuo Masuho; Ryoji Kise; Pablo Gainza; Ee Von Moo; Xiaona Li; Ryosuke Tany; Hideko Wakasugi-Masuho; Bruno E. Correia; Kirill A. Martemyanov

Cell Reports (Oct 2023)

Rules and mechanisms governing G protein coupling selectivity of GPCRs

Ikuo Masuho,
Ryoji Kise,
Pablo Gainza,
Ee Von Moo,
Xiaona Li,
Ryosuke Tany,
Hideko Wakasugi-Masuho,
Bruno E. Correia,
Kirill A. Martemyanov

Affiliations

Ikuo Masuho: Department of Neuroscience, UF Scripps Biomedical Research, Jupiter, FL 33458, USA; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA; Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57105, USA; Corresponding author
Ryoji Kise: Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
Pablo Gainza: Laboratory of Protein Design and Immunoengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland
Ee Von Moo: Department of Neuroscience, UF Scripps Biomedical Research, Jupiter, FL 33458, USA
Xiaona Li: Department of Neuroscience, UF Scripps Biomedical Research, Jupiter, FL 33458, USA
Ryosuke Tany: Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
Hideko Wakasugi-Masuho: Department of Neuroscience, UF Scripps Biomedical Research, Jupiter, FL 33458, USA; Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD 57104, USA
Bruno E. Correia: Laboratory of Protein Design and Immunoengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne and Swiss Institute of Bioinformatics, Lausanne, Switzerland
Kirill A. Martemyanov: Department of Neuroscience, UF Scripps Biomedical Research, Jupiter, FL 33458, USA; Corresponding author

Journal volume & issue: Vol. 42, no. 10
p. 113173

Abstract

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Summary: G protein-coupled receptors (GPCRs) convert extracellular stimuli into intracellular signaling by coupling to heterotrimeric G proteins of four classes: Gi/o, Gq, Gs, and G12/13. However, our understanding of the G protein selectivity of GPCRs is incomplete. Here, we quantitatively measure the enzymatic activity of GPCRs in living cells and reveal the G protein selectivity of 124 GPCRs with the exact rank order of their G protein preference. Using this information, we establish a classification of GPCRs by functional selectivity, discover the existence of a G12/13-coupled receptor, G15-coupled receptors, and a variety of subclasses for Gi/o-, Gq-, and Gs-coupled receptors, culminating in development of the predictive algorithm of G protein selectivity. We further identify the structural determinants of G protein selectivity, allowing us to synthesize non-existent GPCRs with de novo G protein selectivity and efficiently identify putative pathogenic variants.

CP: Cell biology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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