Characterization of a Novel Mammalian RGS Protein That Binds to Gα Proteins and Inhibits Pheromone Signaling in Yeast

Chen, Canhe; Zheng, Bin; Han, Jiahuai; Lin, Sheng-Cai

doi:10.1074/jbc.272.13.8679

Cited by 158 publications

(164 citation statements)

References 34 publications

(51 reference statements)

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“…The hRGS5 was abundantly expressed in heart, lung, skeletal muscle, and small intestine, and at low levels in brain, placenta, liver, colon, and leukocytes. These observations are similar to findings for mouse RGS5 (Chen et al 1997). Recently, the localization of nine rat RGSs, including RGS5, was investigated systematically in rat brain, using an in-situ hybridization technique; the RGS5 mRNA was expressed at lower density in rat brain than in the other tissues examined (Gold et al 1997).…”

Section: Resultssupporting

confidence: 67%

“…The nucleotide sequence data reported here will appear in the DDBJ, EMBL and GenBank nucleotide sequence databases with the accession number AB008109. A homology search of the conceptual translated amino acid sequence of the isolated cDNA revealed that it was most homologous to mouse RGS5 (Chen et al 1997), having 90% identity at the amino acid level, and thus we judged this clone was derived from the human RGS5 (hRGS5) gene. The alignment of the deduced amino acid sequences of hRGS5, mouse RGS5, and rat RGS5 (partial sequence) (Druey et al 1996) is shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

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Isolation, tissue expression, and chromosomal assignment of human RGS5, a novel G-protein signaling regulator gene

Seki¹,

Sugano

Suzuki

et al. 1998

J Hum Genet

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The regulator of G-protein signaling (RGS) proteins have recently been identified as signal transduction molecules which have structural homology to SST2 of Saccharomyces cerevisiae and EGL-10 of Caenorhabditis elegans. Multiple genes homologous to SST2 are present in higher eukaryotes, and the group of these genes is termed the RGS family. RGS proteins are involved in the regulation of heterotrimeric G-proteins by acting as GTPase-activators. A putative new member of the RGS family was isolated from a neuroblastoma cDNA library. The amino acid sequence deduced from the cDNA possessed all consensus motifs of the RGS domain and showed closest homology to mouse RGS5 (90% identical), indicating that it was human RGS5 (hRGS5). The messenger RNA of hRGS5 was abundantly expressed in heart, lung, skeletal muscle, and small intestine, and at low levels in brain, placenta, liver, colon, and leukocytes. The chromosome localization of the gene in the 1q23 region was determined by a monochromosomal hybrid panel and a radiation hybrid panel.

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Section: Resultssupporting

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Isolation, tissue expression, and chromosomal assignment of human RGS5, a novel G-protein signaling regulator gene

Seki¹,

Sugano

Suzuki

et al. 1998

J Hum Genet

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“…Other RGS proteins may contain a similar functional N-terminal domain. Although localization of the mutant protein was not reported, deletion of the Nterminal 13-aa residues of mouse RGS16 renders the protein nonfunctional in yeast (8). Indeed, the sequence conservation in the N-terminal 30 aa of RGS4, RGS5, and RGS16 suggests that this region codes for a functionally important domain (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…A recently appreciated form of regulation has come from the discovery that members of a protein family called regulators of G protein signaling, or RGS proteins, stimulate the rate of GTP hydrolysis by G protein ␣ subunits (3)(4)(5). RGS proteins are found in species ranging from yeast to mammals and constitute a family of at least 20 mammalian proteins (6)(7)(8).…”

mentioning

confidence: 99%

Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae

Srinivasa

Bernstein

Blumer

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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RGS4, a mammalian GTPase activating protein for G protein ␣ subunits, was identified by its ability to inhibit the pheromone response pathway in Saccharomyces cerevisiae. To define regions of RGS4 necessary for its function in vivo, we assayed mutants for activity in this system. Deletion of the N-terminal 33 aa of RGS4 (⌬1-33) yielded a nonfunctional protein and loss of plasma membrane localization. These functions were restored by addition of a C-terminal membrane-targeting sequence to RGS4 (⌬1-33). Thus, plasma membrane localization is tightly coupled with the ability of RGS4 to inhibit signaling. Fusion of the N-terminal 33 aa of RGS4 to green f luorescent protein was sufficient to localize an otherwise soluble protein to the plasma membrane, defining this N-terminal region as a plasma membrane anchorage domain. RGS4 is palmitoylated, with Cys-2 and Cys-12 the likely sites of palmitoylation. Surprisingly, mutation of the cysteine residues within the N-terminal domain of RGS4 did not affect plasma membrane localization in yeast or the ability to inhibit signaling. Features of the N-terminal domain other than palmitoylation are responsible for the plasma membrane association of RGS4 and its ability to inhibit pheromone response in yeast.Heterotrimeric G proteins couple receptors for hormones, neurotransmitters, and sensory signals to intracellular effector molecules, thereby eliciting cellular responses (1, 2). Guanine nucleotide exchange and hydrolysis on the G protein ␣ subunit drives the cycle of activation and deactivation of these signaling pathways. The duration of G protein-mediated responses is subject to the intrinsic GTPase rate of the G protein ␣ subunit, but is also modulated by extrinsic factors. A recently appreciated form of regulation has come from the discovery that members of a protein family called regulators of G protein signaling, or RGS proteins, stimulate the rate of GTP hydrolysis by G protein ␣ subunits (3-5). RGS proteins are found in species ranging from yeast to mammals and constitute a family of at least 20 mammalian proteins (6-8).All RGS family members share sequence similarity that extends over approximately 130 aa, separated in some cases by insertions of varying length (9-11). This conserved RGS domain is sufficient to stimulate GTPase activity of G protein ␣ subunits in vitro (12)(13)(14). Expression of the RGS homology domain of RET-RGS1 or RGS4 yields a recombinant protein that is a functional GAP (GTPase-activating protein). In the crystal structure of RGS4 bound to AlF 4 Ϫ -activated G i␣1 , only the core domain is visible (15). The RGS homology domain binds to the switch regions of G i␣1 and appears to catalyze GTP hydrolysis by stabilizing the switch regions of the G protein in a conformation that favors the transition state of the reactants (14, 15). Sequences outside the RGS homology domain exhibit considerable diversity among family members.Although rapid progress has been made in dissecting the biochemical mechanism by which RGS proteins regulate G protein a...

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“…Moreover, RGS16 knockout leads to the loss of circadian production of cAMP in the SCN [9], implying an intimate link between RGS16 and Gpr176. Biochemically, RGS16 functions as a GTPaseaccelerating protein (GAP) for Gi [37][38][39]. By promoting GTP hydrolysis, RGS16 terminates GTP-bound Gi signaling.…”

Section: The Scn-gene Project Identifies Rgs16 As a Gap Required For mentioning

confidence: 99%

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

et al. 2017

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Abstract. G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development. Here, we review a recently identified role of Gpr176 in the SCN. Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock in the SCN. Even without known ligand, this orphan receptor has an agonist-independent basal activity to reduce cAMP signaling. A unique cAMP-repressing G-protein subclass Gz is required for the activity of Gpr176. We also provide an overview on the circadian regulation of G-protein signaling, with an emphasis on a role for the regulator of G-protein signaling 16 (RGS16). RGS16 is indispensable for the circadian regulation of cAMP in the SCN. Developing drugs that target the SCN remains an unfulfilled opportunity for the circadian pharmacology. This review argues for the potential impact of focusing on GPCRs in the SCN for the purpose of tuning the body clock.

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Characterization of a Novel Mammalian RGS Protein That Binds to Gα Proteins and Inhibits Pheromone Signaling in Yeast

Cited by 158 publications

References 34 publications

Isolation, tissue expression, and chromosomal assignment of human RGS5, a novel G-protein signaling regulator gene

Isolation, tissue expression, and chromosomal assignment of human RGS5, a novel G-protein signaling regulator gene

Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

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