@article{dc5d513b254b4927892a6abd51f3d9c9,
title = "A Global Map of G Protein Signaling Regulation by RGS Proteins",
abstract = "The control over the extent and timing of G protein signaling is provided by the regulator of G protein signaling (RGS) proteins that deactivate G protein α subunits (Gα). Mammalian genomes encode 20 canonical RGS and 16 Gα genes with key roles in physiology and disease. To understand the principles governing the selectivity of Gα regulation by RGS, we examine the catalytic activity of all canonical human RGS proteins and their selectivity for a complete set of Gα substrates using real-time kinetic measurements in living cells. The data reveal rules governing RGS-Gα recognition, the structural basis of its selectivity, and provide principles for engineering RGS proteins with defined selectivity. The study also explores the evolution of RGS-Gα selectivity through ancestral reconstruction and demonstrates how naturally occurring non-synonymous variants in RGS alter signaling. These results provide a blueprint for decoding signaling selectivity and advance our understanding of molecular recognition principles.",
keywords = "BRET, G protein, GPCR, RGS, ancestral reconstitution, cell signaling, genetic variation, protein-protein interaction, striatum",
author = "Ikuo Masuho and Santhanam Balaji and Muntean, {Brian S.} and Skamangas, {Nickolas K.} and Sreenivas Chavali and Tesmer, {John J.G.} and Babu, {M. Madan} and Martemyanov, {Kirill A.}",
note = "Funding Information: We thank Dr. Dipak Patil for helpful discussions, Ms. Hideko Masuho for technical support and data analyses, and Ms. Natalia Martemyanova for assistance with mouse husbandry. This work was supported by NIH grant DA036596 (to K.A.M.), the UKRI Medical Research Council (MC_U105185859, to M.M.B. S.B. and S.C.), and by HL122416, HL071818, and CA221289 (to J.J.G.T.). M.M.B. is a Lister Institute Research Prize Fellow. J.J.G.T. was also supported by the Walther Cancer Foundation, and M.M.B. and S.B. are supported by funding from ALSAC. S.C. was supported by the Ramalingaswami Re-entry Fellowship (BT/RLF/Re-entry/05/2018; SC) from the Department of Biotechnology and by the Science & Engineering Research Board (SRG/2019/001785; SC), Government of India. I.M. participated in project design, performed experiments and data analysis, interpreted the data, and drafted and revised the manuscript; S.B. participated in the project design and data analysis and revised the manuscript; B.S.M. performed experiments and data analysis and drafted the manuscript; N.K.S. performed experiments and data analysis; S.C. performed data analysis; J.J.G.T. made the crystal structure models and interpreted the data; M.M.B. interpreted the data and drafted and revised the manuscript; K.A.M. was responsible for the project design, data interpretation, and manuscript writing. The authors declare no competing interests. Funding Information: We thank Dr. Dipak Patil for helpful discussions, Ms. Hideko Masuho for technical support and data analyses, and Ms. Natalia Martemyanova for assistance with mouse husbandry. This work was supported by NIH grant DA036596 (to K.A.M.), the UKRI Medical Research Council ( MC_U105185859 , to M.M.B., S.B., and S.C.), and by HL122416 , HL071818 , and CA221289 (to J.J.G.T.). M.M.B. is a Lister Institute Research Prize Fellow. J.J.G.T. was also supported by the Walther Cancer Foundation , and M.M.B. and S.B. are supported by funding from ALSAC . S.C. was supported by the Ramalingaswami Re-entry Fellowship (BT/RLF/Re-entry/05/2018; SC) from the Department of Biotechnology and by the Science & Engineering Research Board (SRG/2019/001785; SC), Government of India. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = oct,
day = "15",
doi = "10.1016/j.cell.2020.08.052",
language = "English (US)",
volume = "183",
pages = "503--521.e19",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "2",
}