RGS6 and RGS7 Discriminate between the Highly-Similar Gαi and Gαo Proteins Using a Two-Tiered Specificity Strategy
Publication date: Available online 30 May 2019Source: Journal of Molecular BiologyAuthor(s): Ran Israeli, Ali Asli, Meirav Avital-Shacham, Mickey KosloffAbstractRGS6 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 towards 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 towards Gαo. Hence, the exquisite specificity of RGS6 and RGS7 towards 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 member...
Source: Journal of Molecular Biology - Category: Molecular Biology Source Type: research