PROSITE documentation PDOC50877

GoLoco/GPR motif profile

In heterotrimeric G-protein signalling, cell surface receptors (GPCRs) are coupled to membrane-associated heterotrimers comprising a GTP-hydrolyzing subunit G-α and a G-β/G-γ dimer. The inactive form contains the α subunit bound to GDP and complexes with the β and γ subunit. When the ligand is associated to the receptor, GDP is displaced from G-α and GTP is bound. GTP/G-α complex dissociates from the trimer and associates to an effector until the intrinsic GTPase activity of G-α returns the protein to GDP bound form. Reassociation of GDP bound G-α with G-β/G-γ dimer terminates the signal. Several mechanisms regulate the signal output at different stage of the G-protein cascade. Two classes of intracellular proteins act as inhibitors of G protein activation: GTPase activating proteins (GAPs), which enhance GTP hydrolysis (see <PDOC50132>), and guanine dissociation inhibitors (GDIs), which inhibit GDP dissociation. The GoLoco or G-protein regulatory (GPR) motif found in various G-protein regulators [1,2] acts as a GDI on G-α(i) [3,4,5].

The crystal structure of the GoLoco motif in complex with G-α(i) has been solved (see <PDB:1KJY>) [6]. It consists of three small α helices. The highly conserved Asp-Gln-Arg triad within the GoLoco motif participates directly in GDP binding by extending the arginine side chain into the nucleotide binding pocket, highly reminiscent of the catalytic arginine finger employed in GTPase-activating protein (see <PDOC50238>). This addition of an arginine in the binding pocket affects the interaction of GDP with G-α and therefore is certainly important for the GoLoco GDI activity [6,7].

Some proteins known to contain a GoLoco motif are listed below:

• Mammalian regulators of G-protein signaling 12 and 14 (RGS12 and RGS14), multifaceted signal transduction regulators.
• Loco, the drosophila RGS12 homologue.
• Mammalian Purkinje-cell protein-2 (Pcp2). It may function as a cell-type specific modulator for G protein-mediated cell signaling. It is uniquely expressed in cerebellar Purkinje cells and in retinal bipolar neurons.
• Eukaryotic Rap1GAP. A GTPase activator for the nuclear ras-related regulatory protein RAP-1A.
• Drosophila protein Rapsynoid (also known as Partner of Inscuteable, Pins) and its mammalian homologues AGS3 and LGN. They form a G-protein regulator family that also contains TPR repeats.

The profile we developed covers the whole conserved region.