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 journalArticlepeer-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 languageEnglish (US)
Pages (from-to)503-521.e19
JournalCell
Volume183
Issue number2
DOIs
StatePublished - Oct 15 2020
Externally publishedYes

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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