Structural determinants of G-protein α subunit selectivity by regulator of G-protein signaling 2 (RGS2)

Adam J. Kimple, Meera Soundararajan, Stephanie Q. Hutsell, Annette K. Roos, Daniel J. Urban, Vincent Setola, Brenda R.S. Temple, Bryan L. Roth, Stefan Knapp, Francis S. Willard, David P. Siderovski

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

"Regulator of G-protein signaling" (RGS) proteins facilitate the termination of G protein-coupled receptor (GPCR) signaling via their ability to increase the intrinsic GTP hydrolysis rate of Gα subunits (known as GTPase-accelerating protein or "GAP" activity). RGS2 is unique in its in vitro potency and selectivity as a GAP for Gαq subunits. As many vasoconstrictive hormones signal via Gq heterotrimer-coupled receptors, it is perhaps not surprising that RGS2-deficient mice exhibit constitutive hypertension. However, to date the particular structural features within RGS2 determining its selectivity for Gαq over Gα i/o substrates have not been completely characterized. Here, we examine a trio of point mutations to RGS2 that elicits Gαi-directed binding and GAP activities without perturbing its association with Gαq. Using x-ray crystallography, we determined a model of the triple mutant RGS2 in complex with a transition state mimetic form of Gαi at 2.8-Å resolution. Structural comparison with unliganded, wild type RGS2 and of other RGS domain/Gα complexes highlighted the roles of these residues in wild type RGS2 that weaken Gαi subunit association. Moreover, these three amino acids are seen to be evolutionarily conserved among organisms with modern cardiovascular systems, suggesting that RGS2 arose from the R4-subfamily of RGS proteins to have specialized activity as a potent and selective Gαq GAP that modulates cardiovascular function.

Original languageEnglish
Pages (from-to)19402-19411
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number29
DOIs
StatePublished - 17 Jul 2009

Fingerprint Dive into the research topics of 'Structural determinants of G-protein α subunit selectivity by regulator of G-protein signaling 2 (RGS2)'. Together they form a unique fingerprint.

  • Cite this

    Kimple, A. J., Soundararajan, M., Hutsell, S. Q., Roos, A. K., Urban, D. J., Setola, V., Temple, B. R. S., Roth, B. L., Knapp, S., Willard, F. S., & Siderovski, D. P. (2009). Structural determinants of G-protein α subunit selectivity by regulator of G-protein signaling 2 (RGS2). Journal of Biological Chemistry, 284(29), 19402-19411. https://doi.org/10.1074/jbc.M109.024711