Ags3

AGS3 (activator of G-protein signaling 3), or GPSM1 (NM_144745), was isolated from the neuroblastoma–glioma hybrid cell line NG108-15 by using a functional screen in a yeast strain expressing mammalian Gα_i3 sequences in place of the yeast Gα to identify receptor-independent activators of heterotrimeric G-protein signaling. AGS3 (a 650 amino-acid protein) consists of two functional domains defined by a series of seven amino-terminal tetratrico peptide repeats (TPRs) and four carboxy-terminal G-protein Regulatory (GPR) or GoLoco motifs. Each of the GPR motifs binds to G_iα1–3 and Gα_o, whereas the TPR domain is a site for binding regulatory proteins. The interaction of GPR motifs with G_i/oα stabilizes the GDP-bound conformation of Gα and competes with Gβγ for binding to G_iα. GPR peptides may promote dissociation of Gα and Gβγ independently of nucleotide exchange and can serve as alternative binding partners for α_i•GDP free of Gβγ. AGS3 is a member of the Group II Activators of G-protein signaling, which possess one or more G-protein regulatory (GPR) motifs, which have revealed surprising, unpredicted, functional roles for the ‘G-switch’ in flies, worms and vertebrates. Group II AGS proteins include AGS3, AGS5 or LGN, AGS4 and AGS6 or RGS12, with GPR motifs also found in RGS14 and Pcp2/L7. AGS3, AGS5 and the Drosophila melanogaster ortholog Pins have a similar domain organization with seven tetratricopeptide repeats and up to four GPR motifs. Functional studies with these proteins indicate that their interaction with Gα and control of the ‘G-switch’ provide important signals required for asymmetric cell division, neuronal development and/or synaptic plasticity.