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

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

doi:10.1016/j.jmb.2019.05.037

Cited by 7 publications

(3 citation statements)

References 52 publications

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“…Neuritin 1 (NRN1; downregulated) is involved in neuronal plasticity and associated with neurofibrillary tangles 44 and was the sixth most altered gene in AD. The G protein regulating gene, RGS7 (downregulated) ranked as the seventh most disrupted gene and has been linked to multiple neuronal disorders 45 . While the majority of dysregulated genes are likely to have a contributory effect on AD, in future studies it will be important to evaluate which gene patterns are the most causative and which (if any) may seem like a dysregulation but are neuroprotective.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

Hill

Gammie

2022

Sci Rep

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Alzheimer’s disease (AD) is a complex neurodegenerative disorder that affects multiple brain regions and is difficult to treat. In this study we used 22 AD large-scale gene expression datasets to identify a consistent underlying portrait of AD gene expression across multiple brain regions. Then we used the portrait as a platform for identifying treatments that could reverse AD dysregulated expression patterns. Enrichment of dysregulated AD genes included multiple processes, ranging from cell adhesion to CNS development. The three most dysregulated genes in the AD portrait were the inositol trisphosphate kinase, ITPKB (upregulated), the astrocyte specific intermediate filament protein, GFAP (upregulated), and the rho GTPase, RHOQ (upregulated). 41 of the top AD dysregulated genes were also identified in a recent human AD GWAS study, including PNOC, C4B, and BCL11A. 42 transcription factors were identified that were both dysregulated in AD and that in turn affect expression of other AD dysregulated genes. Male and female AD portraits were highly congruent. Out of over 250 treatments, three datasets for exercise or activity were identified as the top three theoretical treatments for AD via reversal of large-scale gene expression patterns. Exercise reversed expression patterns of hundreds of AD genes across multiple categories, including cytoskeleton, blood vessel development, mitochondrion, and interferon-stimulated related genes. Exercise also ranked as the best treatment across a majority of individual region-specific AD datasets and meta-analysis AD datasets. Fluoxetine also scored well and a theoretical combination of fluoxetine and exercise reversed 549 AD genes. Other positive treatments included curcumin. Comparisons of the AD portrait to a recent depression portrait revealed a high congruence of downregulated genes in both. Together, the AD portrait provides a new platform for understanding AD and identifying potential treatments for AD.

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Section: Discussionmentioning

confidence: 99%

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

Hill

Gammie

2022

Sci Rep

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“…Previous studies explored the role of electrostatic interactions in specifying the selectivity of Ga recognition by several RGS proteins across all of the subfamilies (Asli et al, 2018;Israeli et al, 2019;Kosloff et al, 2011;Salem-Mansour et al, 2018). Collectively, these studies reported 12 amino acid residues in RGS proteins that influence their ability to recognize Ga. Mutation of these residues either alone or in combination (up to 7 simultaneously) was shown to either increase or decrease the GAP activity of RGS proteins on the Ga substrates of choice.…”

Section: Ll Open Accessmentioning

confidence: 99%

A Global Map of G Protein Signaling Regulation by RGS Proteins

Masuho

Balaji

Muntean

et al. 2020

Cell

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“…Indeed, previous studies from our lab showed that "disruptor residues" in the RGS R12 subfamily contribute to interaction specificity by reducing GAP activity towards Gαo, and that this effect is mediated via specific and unfavorable interactions with the Gα helical domain (Asli, Sadiya et al 2018). Subsequent studies showed that such specific attenuation of RGS GAP activity towards members of the Gi subfamily can also occur in the RGS RZ, R4, and R7 subfamilies, in all cases mediated by disruptive interactions with the Gα helical domain (Salem-Mansour, Asli et al 2018, Israeli, Asli et al 2019, Asli, Higazy-Mreih et al 2021). The Gα helical domain was also shown to be the major determinant of the exquisite specificity of RGS2 towards Gαq, preventing interactions with the Gi subfamily (Kasom, Gharra et al 2018).…”

Section: Introductionmentioning

confidence: 99%

Gα_s-specific structural elements attenuate interactions with RGS proteins

Higazy-Mreih,

Avital-Shacham,

LeGouill

et al. 2024

Preprint

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Heterotrimeric (αβγ) G proteins are molecular switches that are activated by G protein-coupled receptors (GPCRs) and regulate numerous intracellular signaling cascades. Most active Gα subunits are inactivated by Regulators of G protein Signaling (RGS) proteins, which determine the duration of G protein-mediated signaling by accelerating the catalytic turn-off of the Gα subunit. However, the G protein Gαs does not interact with known RGS proteins. To understand the molecular basis for this divergent phenomenon, we combined a comparative structural analysis of experimental and modelled structures with functional biochemical assays. This analysis showed that Gαs contains unique structural elements in both the helical and the GTPase domains. Modeling identified helical domain insertions, missing in experimental structures, that project towards the interface with RGS proteins, and residues in the GTPase domain that might interfere with RGS binding. Mutagenesis of Gαs and measurements of RGS GAP activity showed that three residues in the Gαs GTPase domain are both necessary and sufficient to prevent Gαs inactivation by RGSs. Indeed, substitution of all three Gαs residues with the corresponding residues from Gαi1 enabled efficient inactivation by RGS proteins. These results shed new light on the mechanistic bases for G protein specificity towards RGS proteins.

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

Cited by 7 publications

References 52 publications

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

A Global Map of G Protein Signaling Regulation by RGS Proteins

Gα_s-specific structural elements attenuate interactions with RGS proteins

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

Cited by 7 publications

References 52 publications

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

Alzheimer’s disease large-scale gene expression portrait identifies exercise as the top theoretical treatment

A Global Map of G Protein Signaling Regulation by RGS Proteins

Gαs-specific structural elements attenuate interactions with RGS proteins

Contact Info

Product

Resources

About

Gα_s-specific structural elements attenuate interactions with RGS proteins