RGS6 and RGS7 Discriminate between the Highly Similar Gαi and Gαo Proteins Using a Two-Tiered Specificity Strategy

Ran Israeli, Ali Asli, Meirav Avital-Shacham, Mickey Kosloff

Research output: Contribution to journalArticlepeer-review

Abstract

RGS6 and RGS7 are regulators of G protein signaling (RGS) proteins that inactivate heterotrimeric (αβγ) G proteins and mediate diverse biological functions, such as cardiac and neuronal signaling. Uniquely, both RGS6 and RGS7 can discriminate between Gαo and Gαi1—two similar Gα subunits that belong to the same Gi sub-family. Here, we show that the isolated RGS domains of RGS6 and RGS7 are sufficient to achieve this specificity. We identified three specific RGS6/7 “disruptor residues” that can attenuate RGS interactions toward Gα subunits and demonstrated that their insertion into a representative high-activity RGS causes a significant, yet non-specific, reduction in activity. We further identified a unique “modulatory” residue that bypasses this negative effect, specifically toward Gαo. Hence, the exquisite specificity of RGS6 and RGS7 toward closely related Gα subunits is achieved via a two-tier specificity system, whereby a Gα-specific modulatory motif overrides the inhibitory effect of non-specific disruptor residues. Our findings expand the understanding of the molecular toolkit used by the RGS family to achieve specific interactions with selected Gα subunits—emphasizing the functional importance of the RGS domain in determining the activity and selectivity of RGS R7 sub-family members toward particular Gα subunits.

Original languageEnglish
Pages (from-to)3302-3311
Number of pages10
JournalJournal of Molecular Biology
Volume431
Issue number17
DOIs
StatePublished - 9 Aug 2019

Bibliographical note

Funding Information:
We thank Liza Barki-Harrington for helpful comments. This work was supported by the Israel Science Foundation (grants 1454/13 , 1959/13 , and 2155/15 ).

Publisher Copyright:
© 2019 Elsevier Ltd

Keywords

  • G protein signaling
  • PPI
  • RGS proteins
  • interaction specificity
  • protein structure

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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