A Global Map of G Protein Signaling Regulation by RGS Proteins

Ikuo Masuho; Santhanam Balaji; Brian S. Muntean; Nickolas K. Skamangas; Sreenivas Chavali; John J.G. Tesmer; M. Madan Babu; Kirill A. Martemyanov

doi:10.1016/j.cell.2020.08.052

A Global Map of G Protein Signaling Regulation by RGS Proteins

Ikuo Masuho, Santhanam Balaji, Brian S. Muntean, Nickolas K. Skamangas, Sreenivas Chavali, John J.G. Tesmer, M. Madan Babu, Kirill A. Martemyanov

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

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.

Original language	English (US)
Pages (from-to)	503-521.e19
Journal	Cell
Volume	183
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2020.08.052
State	Published - Oct 15 2020
Externally published	Yes

Keywords

BRET
G protein
GPCR
RGS
ancestral reconstitution
cell signaling
genetic variation
protein-protein interaction
striatum

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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@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. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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",

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T1 - A Global Map of G Protein Signaling Regulation by RGS Proteins

AU - Masuho, Ikuo

AU - Balaji, Santhanam

AU - Muntean, Brian S.

AU - Skamangas, Nickolas K.

AU - Chavali, Sreenivas

AU - Tesmer, John J.G.

AU - Babu, M. Madan

AU - Martemyanov, Kirill A.

N1 - 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: © 2020 Elsevier Inc. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2020/10/15

Y1 - 2020/10/15

N2 - 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.

AB - 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.

KW - BRET

KW - G protein

KW - GPCR

KW - RGS

KW - ancestral reconstitution

KW - cell signaling

KW - genetic variation

KW - protein-protein interaction

KW - striatum

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U2 - 10.1016/j.cell.2020.08.052

DO - 10.1016/j.cell.2020.08.052

M3 - Article

C2 - 33007266

AN - SCOPUS:85092517418

VL - 183

SP - 503-521.e19

JO - Cell

JF - Cell

SN - 0092-8674

IS - 2

ER -

A Global Map of G Protein Signaling Regulation by RGS Proteins

Abstract

Keywords

ASJC Scopus subject areas

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