Residue-level determinants of RGS R4 subfamily GAP activity and specificity towards the Gi subfamily

Ali Asli, Sabreen Higazy-Mreih, Meirav Avital-Shacham, Mickey Kosloff

Research output: Contribution to journalArticlepeer-review


The structural basis for the GTPase-accelerating activity of regulators of G protein signaling (RGS) proteins, as well as the mechanistic basis for their specificity in interacting with the heterotrimeric (αβγ) G proteins they inactivate, is not sufficiently understood at the family level. Here, we used biochemical assays to compare RGS domains across the RGS family and map those individual residues that favorably contribute to GTPase-accelerating activity, and those residues responsible for attenuating RGS domain interactions with Gα subunits. We show that conserved interactions of RGS residues with both the Gα switch I and II regions are crucial for RGS activity, while the reciprocal effects of “modulatory” and “disruptor” residues selectively modulate RGS activity. Our results quantify how specific interactions between RGS domains and Gα subunits are set by a balance between favorable RGS residue interactions with particular Gα switch regions, and unfavorable interactions with the Gα helical domain.

Original languageEnglish
Pages (from-to)6305-6318
Number of pages14
JournalCellular and Molecular Life Sciences
Issue number17-18
StatePublished - Sep 2021

Bibliographical note

Funding Information:
This work was supported by grants from the Israel Science Foundation (Grant Numbers: 1454/13, 1959/13, 2155/15), the Canadian Institutes of Health Research (CIHR), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF), and the Azrieli Foundation (Grant Number 3512/19) and the DS Research Center at the University of Haifa. The authors acknowledge the contributions of COST Actions CM-1207 (GLISTEN), CA-15126 (ARBIEU), and CA-18133 (ERNEST) and iNEXT actions PID 4101 and 6623 to this work.

Funding Information:
We thank John Kehrl (NIH) for RGS3, RGS5, and RGS13 clones, Vadim Arshavsky for the G?o clone, and Anna Bakhman for technical assistance.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.


  • GTPases
  • Protein structure
  • Protein–protein interactions
  • Signal transduction

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Cellular and Molecular Neuroscience
  • Cell Biology


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