2. Academic Validation
  3. A Global Map of G Protein Signaling Regulation by RGS Proteins

A Global Map of G Protein Signaling Regulation by RGS Proteins

  • Cell. 2020 Oct 15;183(2):503-521.e19. doi: 10.1016/j.cell.2020.08.052.
Ikuo Masuho 1,  Santhanam Balaji 2,  Brian S Muntean 1,  Nickolas K Skamangas 1,  Sreenivas Chavali 3,  John J G Tesmer 4,  M Madan Babu 2,  Kirill A Martemyanov 5
Affiliations

Affiliations

  • 1 Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA.
  • 2 MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Departments of Structural Biology and Center for Data Driven Discovery, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • 3 MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK; Department of Biology, Indian Institute of Science Education and Research (IISER) Tirupati, Karakambadi Road, Tirupati 517 507, India.
  • 4 Departments of Biological Sciences and Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907-2054, USA.
  • 5 Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33458, USA. Electronic address: [email protected].
PMID: 33007266 DOI: 10.1016/j.cell.2020.08.052
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.

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