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.
| Regulator of G-Protein Signaling Domain | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Structure of active conformation of Gi-alpha1[1] | |||||||||
| Identifiers | |||||||||
| Symbol | RGS | ||||||||
| Pfam | PF00615 | ||||||||
| InterPro | IPR000342 | ||||||||
| SMART | RGS | ||||||||
| PROSITE | PDOC50132 | ||||||||
| SCOP2 | 1gia / SCOPe / SUPFAM | ||||||||
| CDD | cd07440 | ||||||||
| Membranome | 36 | ||||||||
| |||||||||
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.[2] 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 (InterPro: IPR001019), which can then re-bind the βγ-dimer (InterPro: IPR001632 InterPro: IPR001770) 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).[3] 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.[4]
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.[5]
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 (InterPro: IPR000591), PDZ for binding to GPCRs (InterPro: IPR001478), PTB for phosphotyrosine-binding (InterPro: IPR006020), RBD for Ras-binding (InterPro: IPR003116), GoLoco for guanine nucleotide inhibitor activity (InterPro: IPR003109), PX for phosphoinositide-binding (InterPro: IPR001683), PXA that is associated with PX (InterPro: IPR003114), PH for phosphatidylinositol-binding (InterPro: IPR001849), and GGL (G protein gamma subunit-like) for binding G protein beta subunits (InterPro: IPR001770 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
editHuman proteins containing this domain include:
See also
editGTP-binding protein regulators:
References
edit- ^ Coleman DE, Berghuis AM, Lee E, Linder ME, Gilman AG, Sprang SR (September 1994). "Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis". Science. 265 (5177): 1405–12. doi:10.1126/science.8073283. PMID 8073283.
- ^ De Vries L, Farquhar MG, Zheng B, Fischer T, Elenko E (2000). "The regulator of G protein signaling family". Annu. Rev. Pharmacol. Toxicol. 40: 235–271. doi:10.1146/annurev.pharmtox.40.1.235. PMID 10836135.
- ^ Dohlman HG (2009). "Chapter 1 RGS Proteins". RGS proteins the early days. Progress in Molecular Biology and Translational Science. Vol. 86. pp. 1–14. doi:10.1016/S1877-1173(09)86001-8. ISBN 9780123747594. PMID 20374711.
{{cite book}}:|journal=ignored (help) - ^ Burchett SA (2000). "Regulators of G protein signaling: a bestiary of modular protein binding domains". J. Neurochem. 75 (4): 1335–1351. doi:10.1046/j.1471-4159.2000.0751335.x. PMID 10987813.
- ^ Tesmer VM, Kawano T, Shankaranarayanan A, Kozasa T, Tesmer JJ (2005). "Snapshot of activated G proteins at the membrane: the Galphaq-GRK2-Gbetagamma complex". Science. 310 (5754): 1686–1690. doi:10.1126/science.1118890. PMID 16339447. S2CID 11996453.
Further reading
edit- Tesmer, JJ; Berman, DM; Gilman, AG; Sprang, SR (1997). "Structure of RGS4 bound to AlF4--activated G(i alpha1): Stabilization of the transition state for GTP hydrolysis". Cell. 89 (2): 251–61. doi:10.1016/s0092-8674(00)80204-4. PMID 9108480. S2CID 2628150.
- Hunt TW, Fields TA, Casey PJ, Peralta EG (September 1996). "RGS10 is a selective activator of G alpha i GTPase activity". Nature. 383 (6596): 175–7. doi:10.1038/383175a0. PMID 8774883. S2CID 4318445.
- Watson N, Linder ME, Druey KM, Kehrl JH, Blumer KJ (September 1996). "RGS family members: GTPase-activating proteins for heterotrimeric G-protein alpha-subunits". Nature. 383 (6596): 172–5. doi:10.1038/383172a0. PMID 8774882. S2CID 4318239.
- Berman DM, Wilkie TM, Gilman AG (August 1996). "GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits". Cell. 86 (3): 445–52. doi:10.1016/S0092-8674(00)80117-8. PMID 8756726. S2CID 12427406.
- Koelle MR, Horvitz HR (January 1996). "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. doi:10.1016/s0092-8674(00)80998-8. PMID 8548815. S2CID 7815240.
- De Vries L, Mousli M, Wurmser A, Farquhar MG (December 1995). "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. doi:10.1073/pnas.92.25.11916. PMC 40514. PMID 8524874.
- Dohlman H, Apaniesk D, Chen Y, Song J, Nusskern D (July 1995). "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. doi:10.1128/MCB.15.7.3635. PMC 230601. PMID 7791771.
- Siderovski DP, Hessel A, Chung S, Mak TW, Tyers M (February 1996). "A new family of regulators of G-protein-coupled receptors?". Curr Biol. 6 (2): 211–2. doi:10.1016/S0960-9822(02)00454-2. PMID 8673468. S2CID 17214806.
