Regulators of G-Protein Signaling and Their Gα Substrates: Promises and Challenges in Their Use as Drug Discovery Targets

Kimple, Adam J.; Bosch, Dustin E.; Giguère, Patrick M.; Siderovski, David P.

doi:10.1124/pr.110.003038

Cited by 215 publications

(213 citation statements)

References 252 publications

(320 reference statements)

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“…Reverse Transcription Polymerase Chain Reaction-The first-strand cDNA was generated from total mRNA extracted from either HeLa or endothelial cells using SuperScript II reverse transcriptase (RT), an engineered version of Moloney murine leukemia virus reverse transcriptase (M-MLVRT) and oligo(dT) [12][13][14][15][16][17][18] following the instructions of the manufacturer (Invitrogen). The RT enzyme was omitted from the cDNA synthesis reaction in the negative (-) control samples.…”

Section: Methodsmentioning

confidence: 99%

“…The "regulator of G protein signaling" (RGS) proteins accelerate the hydrolysis of GTP by the G␣ subunit and, thereby, function as negative regulators of G protein signaling (14). To determine whether PAR1 WT and AKKAA mutant signaling is differentially regulated by RGS proteins, the expression of RGS proteins in the HeLa and human EA.hy926 endothelial cell lines were first profiled using RT-PCR and primers that detect all conventional RGS mRNA transcripts, as described previously (18).…”

Section: Ap-2 Regulates Activated Par1mentioning

confidence: 99%

“…The family of "regulator of G protein signaling" (RGS) proteins function as GTPase-accelerating proteins for heterotrimeric G proteins, which effectively enhance GTP hydrolysis by the G␣-subunit to shut off G protein signaling. The conventional family of RGS proteins includes 22 members that share a central function in regulation of the G i and G q families (14). The R4 family is the largest family of RGS proteins, with many individual members exhibiting overlapping functions in regulation of G␣ subunits in vitro and in distinct cell types (15,16).…”

mentioning

confidence: 99%

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Regulation of Protease-activated Receptor 1 Signaling by the Adaptor Protein Complex 2 and R4 Subfamily of Regulator of G Protein Signaling Proteins

Chen¹,

Siderovski

Neubig

et al. 2014

Journal of Biological Chemistry

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Background:The function of the clathrin adaptor AP-2 in the regulation of GPCR coupling to G protein signaling is not known. Results: AP-2 controls GPCR signaling by modulating receptor surface expression and, unexpectedly, through RGS protein recruitment to G proteins. Conclusion: AP-2 has diverse functions in the regulation of GPCR signaling. Significance: AP-2 provides a new mode of GPCR signal regulation.

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Section: Methodsmentioning

confidence: 99%

Section: Ap-2 Regulates Activated Par1mentioning

confidence: 99%

mentioning

confidence: 99%

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Regulation of Protease-activated Receptor 1 Signaling by the Adaptor Protein Complex 2 and R4 Subfamily of Regulator of G Protein Signaling Proteins

Chen¹,

Siderovski

Neubig

et al. 2014

Journal of Biological Chemistry

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“…However, it is reminiscent of the activation of a monomeric G protein by its regulator protein RGS (regulator of G protein signaling). The G protein contains the complete set of catalytic residues, and RGS binding locks the flexible switch regions of G into their transition state conformations, promoting GTPase activity 36 . In particular, a conserved asparagine from RGS orients a catalytic glutamine in G that is essential for transition state stabilization (Supplementary Fig.…”

Section: Mechanism Of Srp-gtpase Activation Is Conservedmentioning

confidence: 99%

Structural basis for the molecular evolution of SRP-GTPase activation by protein

Bange

Kümmerer

Grudnik

et al. 2011

Nat Struct Mol Biol

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SIMIBI-class (named after the signal recognition particle, MinD, BioD) nucleotide-binding proteins appeared early in evolution 1 and contain GTPases, as well as ATPases, involved in the correct localization of cellular constituents. The MinD ATPase, as the central part of the Min system, regulates the determination of the cell division site in all bacterial species 2 . SRP-GTPases form a subfamily of the SIMIBI class, with only three members: the signal sequence-binding protein Ffh (SRP54 in Eukarya and Archaea), the SRP receptor FtsY (SR in Eukarya) and FlhF, which is involved in flagella biosynthesis [3][4][5] . They share the conserved NG domain, which contains two major additions to the conserved fold of small G proteins. First, an --element (I-box) is inserted in the effector region; second, the N domain, comprising four -helices, is attached to the N terminus of the G domain. SRP (Ffh together with the SRP RNA) and FtsY constitute the universally conserved co-translational protein-targeting machinery 6,7 . When bound to GTP, Ffh and FtsY form, through interactions between their NG domains 8,9 , a heterodimeric complex that regulates the transfer of a ribosome-nascent chain complex to a vacant translocon in the membrane with a series of conformational rearrangements 10,11 . The two GTPases share a composite active site between their G domains in which GTP hydrolysis is reciprocally activated 12 . The SRP RNA [13][14][15] and membrane lipids 16,17 play fundamental roles in activating the Ffh-FtsY GTPases. The recent structure of the SRP-FtsY complex, together with biochemical implications, suggest that the distal end of the hairpin-like SRP RNA may be involved in this activation 18 . The third SRP-GTPase FlhF, together with the MinD-type protein YlxH (also known as FlhG, FleN, motR or MinD2), is essential for the placement and assembly of flagella 19 in many polar and peritrichous flagellated bacteria [20][21][22][23][24] . FlhF is required for the targeting of the first flagellar protein, FliF, to the cell pole 25 by a mechanism that is so far poorly understood. FlhF is associated with the membrane 25,26 and localizes at the cell pole 20 . The FlhF protein (Fig. 1a) contains an N-terminal B domain that seems to be involved in FliF targeting 25 ; it shares the NG domain fold with the other two members of the SRP-GTPase subfamily. FlhF forms a stable homodimer with GTP and a composite active site that is basically identical to the active site of the Ffh-FtsY heterodimer 5 . In both the homo-and heterodimer, the two nucleotides are bound in a head-to-tail manner, with the -phosphate of one nucleotide interacting with the 3 -OH of the ribose moiety of the other. However, for the homo-and heterodimers formed by the three SRP-GTPases, the molecular mechanism of activation is still unknown. We set out to understand the activation of SRPGTPases by studying FlhF. RESULTS The SRP-GTPase FlhF is activated by YlxHAs FlhF (Fig. 1) forms a stable homodimer, and reciprocal activation has not been observed 5 , we reasoned ...

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“…Although multiple intracellular modulators are known to regulate G protein activity and GPCR-initiated signaling (43,44), modulators specific to tastant signal transduction are only now being identified (e.g. Refs.…”

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confidence: 99%

Regulator of G-protein Signaling-21 (RGS21) Is an Inhibitor of Bitter Gustatory Signaling Found in Lingual and Airway Epithelia

Cohen

Buckley

Kosloff

et al. 2012

Journal of Biological Chemistry

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Background: RGS21 is expressed in tastant-responsive lingual epithelium, but with unknown function. Results: RGS21 accelerated intrinsic GTPase activity of multiple G␣ subunits; RGS21 over-and underexpression in epithelial cells modulated bitterant responsiveness. Conclusion: RGS21 is a negative regulator of bitterant signal transduction. Significance: RGS21 represents a nonreceptor regulatory component of gustatory signaling that alters sensitivity of bitterant responsiveness in an endogenous, cellular context.

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Regulators of G-Protein Signaling and Their Gα Substrates: Promises and Challenges in Their Use as Drug Discovery Targets

Cited by 215 publications

References 252 publications

Regulation of Protease-activated Receptor 1 Signaling by the Adaptor Protein Complex 2 and R4 Subfamily of Regulator of G Protein Signaling Proteins

Regulation of Protease-activated Receptor 1 Signaling by the Adaptor Protein Complex 2 and R4 Subfamily of Regulator of G Protein Signaling Proteins

Structural basis for the molecular evolution of SRP-GTPase activation by protein

Regulator of G-protein Signaling-21 (RGS21) Is an Inhibitor of Bitter Gustatory Signaling Found in Lingual and Airway Epithelia

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