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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]
Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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DbLabel: Engineering Source
An: 43927049
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PubType: Academic Journal
PubTypeId: academicJournal
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  Data: Structural Determinants of G-protein α Subunit Selectivity by Regulator of G-protein Signaling 2 (RGS2).
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  Data: <searchLink fieldCode="AR" term="%22Kimple%2C+Adam+J%2E%22">Kimple, Adam J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Soundararajan%2C+Meera%22">Soundararajan, Meera</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22HutseII%2C+Stephanie+Q%2E%22">HutseII, Stephanie Q.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Roos%2C+Annette+K%2E%22">Roos, Annette K.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Urbän%2C+Daniel+J%2E%22">Urbän, Daniel J.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Setola%2C+Vincent%22">Setola, Vincent</searchLink><relatesTo>1,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Temple%2C+Brenda+R%2E+S%2E%22">Temple, Brenda R. S.</searchLink><relatesTo>3,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Roth%2C+Bryan+L%2E%22">Roth, Bryan L.</searchLink><relatesTo>1,4</relatesTo><br /><searchLink fieldCode="AR" term="%22Knapp%2C+Stefan%22">Knapp, Stefan</searchLink><relatesTo>2,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Willard%2C+Francis+S%2E%22">Willard, Francis S.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Siderovski%2C+David+P%2E%22">Siderovski, David P.</searchLink><relatesTo>1,7</relatesTo><i> dsiderov@med.unc.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Journal+of+Biological+Chemistry%22">Journal of Biological Chemistry</searchLink>. 7/17/2009, Vol. 284 Issue 29, p19402-19411. 10p. 6 Graphs.
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  Data: <searchLink fieldCode="DE" term="%22G+proteins%22">G proteins</searchLink><br /><searchLink fieldCode="DE" term="%22Amino+acids%22">Amino acids</searchLink><br /><searchLink fieldCode="DE" term="%22Cardiovascular+system%22">Cardiovascular system</searchLink><br /><searchLink fieldCode="DE" term="%22X-ray+crystallography%22">X-ray crystallography</searchLink><br /><searchLink fieldCode="DE" term="%22Liquid+chromatography%22">Liquid chromatography</searchLink><br /><searchLink fieldCode="DE" term="%22Wavelengths%22">Wavelengths</searchLink>
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  Data: "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]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Journal of Biological Chemistry is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1074/jbc.M109.024711
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        Text: English
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        PageCount: 10
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      – SubjectFull: G proteins
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      – SubjectFull: Amino acids
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      – SubjectFull: Cardiovascular system
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      – SubjectFull: X-ray crystallography
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      – SubjectFull: Liquid chromatography
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      – SubjectFull: Wavelengths
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