Fidelity of G protein β-subunit association by the G protein γ-subunit-like domains of RGS6, RGS7, and RGS11

Several regulators of G protein signaling (RGS) proteins contain a G protein γ-subunit-like (GGL) domain, which, as we have shown, binds to G_β5 subunits. Here, we extend our original findings by describing another GGL-domain-containing RGS, human RGS6. When RGS6 is coexpressed with different G_β subunits, only RGS6 and G_β5 interact. The expression of mRNA for RGS6 and G_β5 in human tissues overlaps. Predictions of α-helical and coiled-coil character within GGL domains, coupled with measurements of G_β binding by GGL domain mutants, support the contention that G_γ-like regions within RGS proteins interact with G_β5 sub-units in a fashion comparable to conventional G_β/G_γ pairings. Mutation of the highly conserved Phe-61 residue of G_γ2 to tryptophan, the residue present in all GGL domains, increases the stability of the G_β5/G_γ2 heterodimer, highlighting the importance of this residue to GGL/G_β5 association.