Journal
CELL
Volume 183, Issue 2, Pages 503-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.08.052
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Funding
- NIH [DA036596]
- UKRI Medical Research Council [MC_U105185859]
- Walther Cancer Foundation
- ALSAC
- Ramalingaswami Re-entry Fellowship from the Department of Biotechnology [BT/RLF/Re-entry/05/2018]
- Science & Engineering Research Board, Government of India [SRG/2019/001785]
- [HL122416]
- [HL071818]
- [CA221289]
- MRC [MC_U105185859] Funding Source: UKRI
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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 a subunits (G alpha). Mammalian genomes encode 20 canonical RGS and 16 G alpha genes with key roles in physiology and disease. To understand the principles governing the selectivity of G alpha regulation by RGS, we examine the catalytic activity of all canonical human RGS proteins and their selectivity for a complete set of G alpha substrates using real-time kinetic measurements in living cells. The data reveal rules governing RGS-G alpha 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-G alpha 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.
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