Structure of the Regulator of G Protein Signaling 8 (RGS8)-Gα q Complex: Molecular Basis for Gα Selectivity
Regulator of G protein signaling (RGS) proteins interact with activated Gα subunits via their RGS domains and accelerate the hydrolysis of GTP. Although the R4 subfamily of RGS proteins generally accepts both Gα i/o and Gα q/11 subunits as substrates, the R7 and R12 subfamilies select against Gα q/11 . In contrast, only one RGS protein, RGS2, is known to be selective for Gαq/11. The molecular basis for this selectivity is not clear. Previously, the crystal structure of RGS2 in complex with Gα q revealed a non-canonical interaction that could be due to interfacial differences imposed by RGS2, the Gα subunit, or both. To resolve this ambiguity, the 2.6 Å crystal structure of RGS8, an R4 subfamily member, was determined in complex with Gα q . RGS8 adopts the same pose on Gα q as it does when bound to Gα i3 , indicating that the non-canonical interaction of RGS2 with Gα q is due to unique features of RGS2. Here, based on the RGS8-Gα q structure, residues in RGS8 that contact a unique α-helical domain loop of Gα q were converted to those typically found in R12 subfamily members, and the reverse substitutions were introduced into RGS10, an R12 subfamily member. Although these substitutions perturbed their ability to stimulate GTP hydrolysis, they did not reverse selectivity. Instead, selectivity for Gα q seems more likely determined by whether strong contacts can be maintained between α6 of the RGS domain and Switch III of Gα q , regions of high sequence and conformational diversity in both protein families.