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
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.
