Regulator of G protein signalling
Encyclopedia
Regulators of G protein signalling (or RGS) are protein structural domains that activate GTPase
s for heterotrimeric G-protein alpha-subunits.
RGS are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways. Upon activation by GPCRs, heterotrimeric G proteins exchange GDP for GTP, are released from the receptor, and dissociate into free, active GTP-bound alpha subunit and beta-gamma dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the alpha subunit , which can then bind the beta-gamma dimer and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound alpha subunits by stabilising the G protein transition state.
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.
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 phosphatidylinositol-binding , PXA that is associated with PX , PH for stimulating guanine nucleotide exchange , 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.
GTPase
GTPases are a large family of hydrolase enzymes that can bind and hydrolyze guanosine triphosphate . The GTP binding and hydrolysis takes place in the highly conserved G domain common to all GTPases.-Functions:...
s for heterotrimeric G-protein alpha-subunits.
RGS are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways. Upon activation by GPCRs, heterotrimeric G proteins exchange GDP for GTP, are released from the receptor, and dissociate into free, active GTP-bound alpha subunit and beta-gamma dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the alpha subunit , which can then bind the beta-gamma dimer and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound alpha subunits by stabilising the G protein transition state.
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.
RGS domains can be found within the same protein in combination with a variety of other domains, including: DEP
DEP domain
In molecular biology, the DEP domain is a globular protein domain of about 80 amino acids that is found in over 50 proteins involved in G-protein signalling pathways...
for membrane targeting , PDZ
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
for binding to GPCRs , PTB for phosphotyrosine-binding , RBD
Raf-like Ras-binding domain
Raf-like Ras-binding domain is an evolutionary conserved protein domain. This is the Ras-binding domain found in proteins related to Ras.- Examples :Human proteins containing this domain include:* ARAF* BRAF* RAF1* RGS12, RGS14* TIAM1...
for Ras
Ras superfamily
The Ras superfamily is a protein superfamily of small GTPases, which are all related, to a degree, to the Ras protein subfamily .There are more than a hundred proteins in the Ras superfamily...
-binding , GoLoco
GoLoco motif
GoLoco motif is a protein structural motif.In heterotrimeric G-protein signalling, cell surface receptors are coupled to membrane-associated heterotrimers comprising a GTP-hydrolyzing subunit G-alpha and a G-beta/G-gamma dimer. The inactive form contains the alpha subunit bound to GDP and...
for guanine nucleotide inhibitor activity , PX
PX domain
The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.This domain was first found in P40phox and p47phox domains of NADPH oxidase...
for phosphatidylinositol-binding , PXA that is associated with PX , PH for stimulating guanine nucleotide exchange , and GGL
GGL domain
GGL domain is domain found in the gamma subunit of the heterotrimeric G protein complex and in regulators of G protein signaling RGS proteins.-Human proteins containing this domain :* GNG4; GNG10; GNG11* GNGT1* RGS6; RGS7; RGS9; RGS11...
(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:- ADRBK1, ADRBK2, AXIN1AXIN1Axin-1 is a protein that in humans is encoded by the AXIN1 gene.-Interactions:AXIN1 has been shown to interact with Beta-catenin, GSK3B, TSC2, APC, LRP5, DVL1, MAP3K1, CSNK1E, Casein kinase 1, alpha 1 and PPP2R5A.-Further reading:...
, AXIN2AXIN2Axin-2 also known as axin-like protein or axis inhibition protein 2 or conductin is a protein that in humans is encoded by the AXIN2 gene.- Function :... - GRK1, GRK4GRK4G protein-coupled receptor kinase 4 is an enzyme that in humans is encoded by the GRK4 gene.-Further reading:...
, GRK5GRK5G protein-coupled receptor kinase 5 is an enzyme that in humans is encoded by the GRK5 gene.-Further reading:...
, GRK6GRK6G protein-coupled receptor kinase 6 is an enzyme that in humans is encoded by the GRK6 gene.-Further reading:...
, GRK7, - RGS1RGS1Regulator of G-protein signaling 1 is a protein that in humans is encoded by the RGS1 gene.-Further reading:...
, RGS2RGS2Regulator of G-protein signaling 2 is a protein that in humans is encoded by the RGS2 gene.-Interactions:RGS2 has been shown to interact with PRKG1 and ADCY5.-Further reading:...
, RGS3RGS3Regulator of G-protein signaling 3 is a protein that in humans is encoded by the RGS3 gene.-Further reading:...
, RGS4RGS4Regulator of G protein signaling 4 or RGS4 is a protein which regulates G protein signaling. A number of studies associate the RGS4 gene with schizophrenia, while some fail to detect an association....
, RGS5RGS5Regulator of G-protein signaling 5 is a protein that in humans is encoded by the RGS5 gene.-Interactions:RGS5 has been shown to interact with GNAO1, GNAI2 and GNAI3.-Further reading:...
, RGS6RGS6Regulator of G-protein signaling 6 is a protein that in humans is encoded by the RGS6 gene.-Interactions:RGS6 has been shown to interact with STMN2 and DMAP1.-Further reading:...
, RGS7RGS7Regulator of G-protein signaling 7 is a protein that in humans is encoded by the RGS7 gene.-Interactions:RGS7 has been shown to interact with PKD1, GNB5 and SNAPAP.-Further reading:...
, RGS8RGS8Regulator of G-protein signaling 8 is a protein that in humans is encoded by the RGS8 gene.-Further reading:...
, RGS9RGS9Regulator of G-protein signalling 9, also known as RGS9, is a human gene, which codes for a protein involved in regulation of signal transduction inside cells...
, RGS10RGS10Regulator of G-protein signaling 10 is a protein that in humans is encoded by the RGS10 gene.-Interactions:RGS10 has been shown to interact with SAP18 and GNAI3.-Further reading:...
, RGS11RGS11Regulator of G-protein signaling 11 is a protein that in humans is encoded by the RGS11 gene.-Further reading:...
, RGS12RGS12Regulator of G-protein signaling 12 is a protein that in humans is encoded by the RGS12 gene.-Interactions:RGS12 has been shown to interact with GNAI1 and GNAI3.-Further reading:...
, RGS13RGS13Regulator of G-protein signaling 13 is a protein that in humans is encoded by the RGS13 gene.RGS 13 is a member of R4 subfamily of RGS proteins which have only short peptide sequences flanking the RGS domain. RGS 13 suppresses the immunoglobulin E- mediated allergic responses.-References:...
, RGS14RGS14Regulator of G-protein signaling 14 is a protein that in humans is encoded by the RGS14 gene.- Function :RGS14 is a member of the regulator of G protein signalling family. This protein contains one RGS domain, two Raf-like Ras-binding domains , and one GoLoco motif...
, RGS16RGS16Regulator of G-protein signaling 16 is a protein that in humans is encoded by the RGS16 gene.-Interactions:RGS16 has been shown to interact with GNAQ and GNAI3.-Further reading:...
, RGS17RGS17Regulator of G-protein signaling 17 is a protein that in humans is encoded by the RGS17 gene.This gene encodes a member of the regulator of G-protein signaling family. This protein contains a conserved, 120 amino acid motif called the RGS domain and a cysteine-rich region...
, RGS18RGS18Regulator of G-protein signaling 18 is a protein that in humans is encoded by the RGS18 gene.-Further reading:...
, RGS19RGS19Regulator of G-protein signaling 19 is a protein that in humans is encoded by the RGS19 gene.-Interactions:RGS19 has been shown to interact with GNAO1, GIPC1, OSTM1, GNAI1, GNAI3 and GNAZ.-Further reading:...
, RGS20RGS20Regulator of G-protein signaling 20 is a protein that in humans is encoded by the RGS20 gene.-Interactions:RGS20 has been shown to interact with GNAO1 and GNAZ.-Further reading:...
, RGS21 - RK
- SNX13SNX13Sorting nexin-13 is a protein that in humans is encoded by the SNX13 gene.-Further reading:...
See also
GTP-binding protein regulators:- GEFGuanine nucleotide exchange factorGuanine nucleotide exchange factors activate monomeric GTPases by stimulating the release of guanosine diphosphate to allow binding of guanosine triphosphate . A variety of unrelated structural domains have been shown to exhibit guanine nucleotide exchange activity...
- GAP
Further reading
- Structure of RGS4 bound to AlF4—activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Tesmer JJ, Berman DM, Gilman AG, Sprang SR; Cell 1997;89:251-261.
External links
- http://prosite.expasy.org/cgi-bin/prosite/prosite-search-ful?SEARCH=rgs in PROSITEPROSITEPROSITE is a protein database. It consists of entries describing the protein families, domains and functional sites as well as amino acid patterns, signatures, and profiles in them. These are manually curated by a team of the Swiss Institute of Bioinformatics and tightly integrated into Swiss-Prot...