PROSITE documentation PDOC50132

RGS domain profile

Regulators of G-protein signaling (RGS) proteins are a family of highly diverse, multifunctional signaling proteins that are found in eukaryotic species ranging from yeast to mammals. They act as GTPase activating proteins (GAPs) that reduce the signal transmitted by the receptor-activated (GTP bound) G-α subunit by rapidly returning it to the inactive state (GDP bound). Although they are a diverse group of proteins, all RGS family members share a conserved 120 amino acid domain, the RGS domain. The RGS domain binds to activated G-α subunits and is responsible for GAP function. Apart from the RGS domain, RGS proteins differ widely in their overall size and amino acid identity and possess a remarkable variety of structural domains and motifs. These additional domains, like DEP (see <PDOC50186>, PDZ (see <PDOC50106> or PH (see <PDOC50003>, link the RGS proteins to other signaling network, where they constitute effector type molecules [1,2,3].

RGS domains are broken up into three highly conserved GH (GAIP or GOS homology) subdomains (GH1, GH2 and GH3), which can be either nearly contiguous or widely dispersed within nonconserved sequences [3]. Resolution of the crystal structure of the RGS4 protein complexed with a stable transition state mimic of G-α-GTP has revealed that the RGS domain forms nine α-helices that fold into two small subdomains. These subdomains each contact the G-α surface at three distinct sites [4].

Some proteins known to contain a RGS domain are listed below:

• Mammalian regulator of G-protein signaling (RGS) proteins.
• Mammalian G-α interacting protein (GAIP).
• Mammalian G-protein-coupled-receptor kinases (GRK), proteins that directly phosphorylate GPCRs to regulate signaling.
• Animal axin/conductin, an inhibitor of the wg/wnt signaling pathway. The RGS domain of axin/conductin interacts with the tumour-suppressor adenomatous polyposis coli (APC), a non-G-α-like molecule, which indicates that some RGS domains can bind to proteins other than G-α.
• Caenorhabditis elegans egl-10, which regulates G protein signaling in nervous system.
• Drosophila Loco, a protein required for glial differentiation.
• Saccharomyces cerevisiae SST2, a negative regulator of the G protein- coupled mating pheromone signaling pathway.

We have developed a profile that covers the entire RGS domain.