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Structural Determinants of G-protein α Subunit Selectivity by Regulator of G-protein Signaling 2 (RGS2).

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Title: Structural Determinants of G-protein α Subunit Selectivity by Regulator of G-protein Signaling 2 (RGS2).
Authors: Kimple, Adam J.1, Soundararajan, Meera2, HutseII, Stephanie Q.3, Roos, Annette K.2, Urbän, Daniel J.1, Setola, Vincent1,4, Temple, Brenda R. S.3,5, Roth, Bryan L.1,4, Knapp, Stefan2,6, Willard, Francis S.1, Siderovski, David P.1,7 dsiderov@med.unc.edu
Source: Journal of Biological Chemistry. 7/17/2009, Vol. 284 Issue 29, p19402-19411. 10p. 6 Graphs.
Subjects: G proteins, Amino acids, Cardiovascular system, X-ray crystallography, Liquid chromatography, Wavelengths
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 Ga subunits (known as GTPase-accelerating protein or "GAP" activity). RGS2 is unique in its in vitro potency and selectivity as a GAP for Gaq 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 Gαi/0 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/Ga 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. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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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 Ga subunits (known as GTPase-accelerating protein or "GAP" activity). RGS2 is unique in its in vitro potency and selectivity as a GAP for Gaq 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 Gαi/0 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/Ga 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. [ABSTRACT FROM AUTHOR]
ISSN:00219258
DOI:10.1074/jbc.M109.024711