Regulator of G protein signaling explained

Regulators of G protein signaling (RGS) are protein structural domains or the proteins that contain these domains, that function to activate the GTPase activity of heterotrimeric G-protein α-subunits.

RGS proteins are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the α-subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signaling pathways.^[1] Upon activation by receptors, G proteins exchange GDP for GTP, are released from the receptor, and dissociate into a free, active GTP-bound α-subunit and βγ-dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the α-subunit, which can then re-bind the βγ-dimer and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound α-subunits by stabilising the G protein transition state. Whereas receptors stimulate GTP binding, RGS proteins stimulate GTP hydrolysis.

RGS proteins have been conserved in evolution. The first to be identified was Sst2 ("SuperSensiTivity to pheromone") in yeast (Saccharomyces cerevisiae).^[2] All RGS proteins contain an RGS-box (or RGS domain), which is required for activity. Some small RGS proteins such as RGS1 and RGS4 are little more than an RGS domain, while others also contain additional domains that confer further functionality.^[3]

RGS domains in the G protein-coupled receptor kinases are able to bind to Gq family α-subunits, but do not accelerate their GTP hydrolysis. Instead, GRKs appear to reduce Gq signaling by sequestering the active α-subunits away from effectors such as phospholipase C-β.^[4]

Plants have RGS proteins but do not have canonical G protein-coupled receptors. Thus G proteins and GTPase accelerating proteins appear to have evolved before any known G protein activator.

RGS domains can be found within the same protein in combination with a variety of other domains, including: DEP for membrane targeting, PDZ for binding to GPCRs, PTB for phosphotyrosine-binding, RBD for Ras-binding, GoLoco for guanine nucleotide inhibitor activity, PX for phosphoinositide-binding, PXA that is associated with PX, PH for phosphatidylinositol-binding, and GGL (G protein gamma subunit-like) for binding G protein beta subunits (Those RGS proteins that contain GGL domains can interact with G protein beta subunits to form novel dimers that prevent G protein gamma subunit binding and G protein alpha subunit association, thereby preventing heterotrimer formation.

Examples

Human proteins containing this domain include:

• AXIN1, AXIN2
• GRK1, GRK2, GRK3, GRK4, GRK5, GRK6, GRK7
• RGS1, RGS2, RGS3, RGS4, RGS5, RGS6, RGS7, RGS8, RGS9, RGS10, RGS11, RGS12, RGS13, RGS14, RGS16, RGS17, RGS18, RGS19, RGS20, RGS21
• SNX13

See also

GTP-binding protein regulators:

• GEF
• GAP

Further reading

• 9108480. 1997. Tesmer. JJ. Berman. DM. Gilman. AG. Sprang. SR. Structure of RGS4 bound to AlF4--activated G(i alpha1): Stabilization of the transition state for GTP hydrolysis. 89. 2. 251–61. Cell. 10.1016/s0092-8674(00)80204-4. 2628150. free.
• Hunt TW, Fields TA, Casey PJ, Peralta EG . RGS10 is a selective activator of G alpha i GTPase activity . Nature . 383 . 6596 . 175–7 . September 1996 . 8774883 . 10.1038/383175a0 . 4318445 .
• Watson N, Linder ME, Druey KM, Kehrl JH, Blumer KJ . RGS family members: GTPase-activating proteins for heterotrimeric G-protein alpha-subunits . Nature . 383 . 6596 . 172–5 . September 1996 . 8774882 . 10.1038/383172a0 . 4318239 .
• Berman DM, Wilkie TM, Gilman AG . GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits . Cell . 86 . 3 . 445–52 . August 1996 . 8756726 . 10.1016/S0092-8674(00)80117-8. 12427406 . free .
• Koelle MR, Horvitz HR . EGL-10 regulates G protein signaling in the C. elegans nervous system and shares a conserved domain with many mammalian proteins . Cell . 84 . 1 . 115–25 . January 1996 . 8548815 . 10.1016/s0092-8674(00)80998-8. 7815240 . free .
• De Vries L, Mousli M, Wurmser A, Farquhar MG . GAIP, a protein that specifically interacts with the trimeric G protein G alpha i3, is a member of a protein family with a highly conserved core domain . Proc. Natl. Acad. Sci. U.S.A. . 92 . 25 . 11916–20 . December 1995 . 8524874 . 40514 . 10.1073/pnas.92.25.11916. free .
• Dohlman H, Apaniesk D, Chen Y, Song J, Nusskern D . Inhibition of G-protein signaling by dominant gain-of-function mutations in Sst2p, a pheromone desensitization factor in Saccharomyces cerevisiae . Mol Cell Biol . 15 . 7 . 3635–43 . July 1995 . 7791771 . 230601 . 10.1128/MCB.15.7.3635 .
• Siderovski DP, Hessel A, Chung S, Mak TW, Tyers M . A new family of regulators of G-protein-coupled receptors? . Curr Biol . 6 . 2 . 211–2 . February 1996 . 8673468 . 10.1016/S0960-9822(02)00454-2. 17214806 . free .

External links

• http://prosite.expasy.org/cgi-bin/prosite/prosite-search-ful?SEARCH=rgs in PROSITE

Notes and References

1. De Vries L, Farquhar MG, Zheng B, Fischer T, Elenko E . The regulator of G protein signaling family . Annu. Rev. Pharmacol. Toxicol. . 40 . 235–271 . 2000 . 10836135 . 10.1146/annurev.pharmtox.40.1.235.
2. Book: Dohlman HG . RGS proteins the early days . Chapter 1 RGS Proteins . Prog. Mol. Biol. Transl. Sci. . 86 . 1–14 . 2009 . 20374711 . 10.1016/S1877-1173(09)86001-8. Progress in Molecular Biology and Translational Science . 9780123747594 .
3. Burchett SA . Regulators of G protein signaling: a bestiary of modular protein binding domains . J. Neurochem. . 75 . 4 . 1335–1351 . 2000 . 10987813 . 10.1046/j.1471-4159.2000.0751335.x.
4. Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJ . Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex . Science . 310 . 5754 . 1686–1690 . 2005 . 16339447 . 10.1126/science.1118890 . 11996453 .