Regulation of G protein signalling in yeast

Dohlman, Henrik G.; Song, Jianping; Apanovitch, Donald M.; DiBello, Paul R.; Gillen, Kathy M.

doi:10.1006/scdb.1998.0218

Seminars in Cell & Developmental Biology

1998

DOI: 10.1006/scdb.1998.0218

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Regulation of G protein signalling in yeast

Henrik G. Dohlman

Jianping Song

Donald M. Apanovitch

et al.

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Cited by 43 publications

(28 citation statements)

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“…In this pathway, a heterotrimeric G protein consisting of the products of the GPA1, STE4, and STE18 genes transmits signals from pheromone receptors to a mitogenactivated protein kinase cascade that regulates gene expression and cell cycle arrest (11). An RGS protein encoded by the SST2 gene is critical for normal signaling in this pathway; loss-of-function mutants increase the sensitivity of cells to mating pheromone and reduce the specificity requirements of the pheromone (9), while overproduction of Sst2p reduces signaling capacity (10).…”

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confidence: 99%

SST2, a Regulator of G-Protein Signaling for theCandida albicansMating Response Pathway

Dignard

Whiteway

2006

Eukaryot Cell

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Candida albicans contains a functional mating response pathway that is similar to the well-studied system of Saccharomyces cerevisiae. We have characterized a regulator of G protein signaling (RGS) homolog in C. albicans with sequence similarity to the SST2 gene of Saccharomyces cerevisiae. Disruption of this gene, which had been designated SST2, causes an opaque MTLa/MTLa derivative of strain SC5314 to show hypersensitivity to the C. albicans ␣-factor. This hypersensitivity generates an enhanced cell cycle arrest detected in halo assays but reduces the overall mating efficiency of the cells. Transcriptional profiling of the pheromone-regulated gene expression in the sst2 mutant shows a pattern of gene induction similar to that observed in wild-type cells, but the responsiveness is heightened. This involvement of an RGS in the sensitivity to pheromone is consistent with the prediction that the mating response pathway in C. albicans requires the activation of a heterotrimeric G protein.

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confidence: 99%

SST2, a Regulator of G-Protein Signaling for theCandida albicansMating Response Pathway

Dignard

Whiteway

2006

Eukaryot Cell

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“…The binding pockets within the transmembrane domains of several bioamine receptors have been identified using this kind of approach. The adenosine A 1 receptor (8) and the ␤ 2 adrenergic receptor (9,10) are typical examples. Peptidergic receptors such as hAT 1 and hAT 2 (11,12), neurokinin receptors (13), and several other receptors from the secretin GPCR family B (14) have been also studied using this approach.…”

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confidence: 99%

Determining the Environment of the Ligand Binding Pocket of the Human Angiotensin II Type I (hAT1) Receptor Using the Methionine Proximity Assay

Clement

Martin

Beaulieu

et al. 2005

Journal of Biological Chemistry

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The peptide hormone angiotensin II (AngII) binds to the AT 1 (angiotensin type 1) receptor within the transmembrane domains in an extended conformation, and its C-terminal residue interacts with transmembrane domain VII at Phe-293/Asn-294. The molecular environment of this binding pocket remains to be elucidated. The preferential binding of benzophenone photolabels to methionine residues in the target structure has enabled us to design an experimental approach called the methionine proximity assay, which is based on systematic mutagenesis and photolabeling to determine the molecular environment of this binding pocket. The octapeptide hormone angiotensin II (AngII) 1 (Fig. 1A) is the active component of the renin-angiotensin system. Virtually all known physiological effects of AngII are produced through the activation of the hAT 1 receptor, which belongs to the class A rhodopsin-like family of the heptahelical G proteincoupled receptor (GPCR) superfamily (1, 2). Elucidating the stereochemistry of the ligand-receptor interaction is vital for understanding the mechanism of ligand binding, GPCR activation, and, eventually, rational drug design.In the past, much effort was devoted to identifying the domains or individual residues of a given receptor that may interact with its ligand. Most experiments to address ligandreceptor interactions were performed with series of receptor mutants to identify specific residues critical to ligand binding (3-5). It is, however, speculative to deduce precise structures of ligand-receptor interactions through mutagenesis studies alone. More direct approaches have therefore been used to study ligand-receptor interactions. Among these is photoaffinity labeling, which allows covalent incorporation of the ligand within its binding site, presumably at the contact area of the photolabel in the receptor. This ligand-receptor contact can be identified by specific enzymatic or chemical digestion of the labeled receptor (6) or by mass spectrometry (7). The binding pockets within the transmembrane domains of several bioamine receptors have been identified using this kind of approach. The adenosine A 1 receptor (8) and the ␤ 2 adrenergic receptor (9, 10) are typical examples. Peptidergic receptors such as hAT 1 and hAT 2 (11, 12), neurokinin receptors (13), and several other receptors from the secretin GPCR family B (14) have been also studied using this approach. We previously identified ligandcontact points within the second extracellular loop (ECL) and the seventh transmembrane domain (TMD) of the hAT 1 receptor (12,15,16). Although photoaffinity labeling has been widely used to study peptidergic GPCR binding pockets, generally only a single contact point between a given ligand and its cognate receptor has been identified. The resulting information does not, however, induce sufficient restrictions to generate credible GPCR structures in the ligand-bound state using homology modeling.Labeling studies using benzophenone residues have identified many ligand-receptor contact points with a surpris...

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“…The RGS domain-containing proteins dramatically enhance the endogenous GTPase activity of G␣ subunits by binding to and stabilizing the flexible switch regions of G␣ to resemble that of the transition state, thereby lowering the activation energy barrier of the hydrolysis reaction (13)(14)(15)(16). RGS proteins have been shown to play an essential role in desensitizing and negatively regulating G protein-mediated responses or accelerating the kinetics of GPCR signal transduction in yeast (17,18), nematode (19,20), and vertebrates (21)(22)(23)(24).…”

mentioning

confidence: 99%

Regulator of G Protein Signaling Z1 (RGSZ1) Interacts with Gαi Subunits and Regulates Gαi-mediated Cell Signaling

Wang

Zhang

et al. 2002

Journal of Biological Chemistry

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Regulator of G protein signaling (RGS) proteins constitute a family of over 20 proteins that negatively regulate heterotrimeric G protein-coupled receptor signaling pathways by enhancing endogenous GTPase activities of G protein ␣ subunits. RGSZ1, one of the RGS proteins specifically localized to the brain, has been cloned previously and described as a selective GTPase accelerating protein for G␣ z subunit. Here, we employed several methods to provide new evidence that RGSZ1 interacts not only with G␣ z, but also with G␣ i , as supported by in vitro binding assays and functional studies. Using glutathione S-transferase fusion protein pulldown assays, glutathione S-transferase-RGSZ1 protein was shown to bind 35 S-labeled G␣ i1 protein in an AlF 4 ؊ dependent manner. The interaction between RGSZ1 and G␣ i was confirmed further by co-immunoprecipitation studies and yeast two-hybrid experiments using a quantitative luciferase reporter gene. Extending these observations to functional studies, RGSZ1 accelerated endogenous GTPase activity of G␣ i1 in single-turnover GTPase assays. Human RGSZ1 functionally regulated GPA1 (a yeast G␣ i -like protein)-mediated yeast pheromone response when expressed in a SST2 (yeast RGS protein) knockout strain. In PC12 cells, transfected RGSZ1 blocked mitogen-activated protein kinase activity induced by UK14304, an ␣ 2 -adrenergic receptor agonist. Furthermore, RGSZ1 attenuated D2 dopamine receptor agonist-induced serum response element reporter gene activity in Chinese hamster ovary cells. In summary, these data suggest that RGSZ1 serves as a GTPase accelerating protein for G␣ i and regulates G␣ i -mediated signaling, thus expanding the potential role of RGSZ1 in G protein-mediated cellular activities.Trimeric guanine nucleotide-binding proteins (G proteins) 1 are key components in transducing extracellular signals into intracellular responses (1-5). The functional activity of G protein ␣ subunit is critically governed by the rates of GDP/GTP exchange stimulated by the receptor activation, and the intrinsic GTPase activity that hydrolyzes the GTP to GDP. However, the in vitro measured intrinsic GTPase activity of G protein ␣ subunits is too slow to account for the rapid signal termination that occurs in vivo. A new family of proteins, regulators of G protein signaling (RGS), have been identified to accelerate the intrinsic GTPase activity of G␣ subunits and mechanistically impact the kinetics of G protein physiological function (6 -12). To date, over 20 mammalian proteins are known to contain the RGS domain, a homologous core domain of 120 amino acids. The RGS domain-containing proteins dramatically enhance the endogenous GTPase activity of G␣ subunits by binding to and stabilizing the flexible switch regions of G␣ to resemble that of the transition state, thereby lowering the activation energy barrier of the hydrolysis reaction (13-16). RGS proteins have been shown to play an essential role in desensitizing and negatively regulating G protein-mediated responses or accelerating the k...

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Regulation of G protein signalling in yeast

Cited by 43 publications

References 0 publications

SST2, a Regulator of G-Protein Signaling for theCandida albicansMating Response Pathway

SST2, a Regulator of G-Protein Signaling for theCandida albicansMating Response Pathway

Determining the Environment of the Ligand Binding Pocket of the Human Angiotensin II Type I (hAT1) Receptor Using the Methionine Proximity Assay

Regulator of G Protein Signaling Z1 (RGSZ1) Interacts with Gαi Subunits and Regulates Gαi-mediated Cell Signaling

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