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>) . 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.
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