5do9

Publication Abstract from PubMed

Regulator of G protein signaling (RGS) proteins interact with activated Galpha subunits via their RGS domains and accelerate the hydrolysis of GTP. Whereas the R4 subfamily of RGS proteins generally accepts both Galphai/o and Galphaq/11 subunits as substrates, the R7 and R12 subfamilies select against Galphaq/11. In contrast, only one RGS protein, RGS2, is known to be selective for Galphaq/11. The molecular basis for this selectivity is not clear. Previously, the crystal structure of RGS2 in complex with Galphaq revealed a non-canonical interaction that could be due to interfacial differences imposed by RGS2, the Galpha subunit, or both. To resolve this ambiguity, the 2.6 A crystal structure of RGS8, an R4 subfamily member, was determined in complex with Galphaq. RGS8 adopts the same pose on Galphaq as it does when bound to Galphai3, indicating that the non-canonical interaction of RGS2 with Galphaq is due to unique features of RGS2. Based on the RGS8 structure, residues in RGS8 that contact a unique alpha-helical domain loop of Galphaq 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 Galphaq seems more likely determined by whether strong contacts can be maintained between alpha of the RGS domain and Switch III of Galphaq, regions of high sequence and conformational diversity in both protein families.

Structure of the Regulator of G Protein Signaling 8 (RGS8)-Galphaq Complex: Molecular Basis for Galpha Selectivity.,Taylor VG, Bommarito PA, Tesmer JJ J Biol Chem. 2016 Jan 11. pii: jbc.M115.712075. PMID:26755720^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.