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Originally published In Press as doi:10.1074/jbc.M212695200 on January 13, 2003

J. Biol. Chem., Vol. 278, Issue 11, 9912-9919, March 14, 2003
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Mapping the Galpha 13 Binding Interface of the rgRGS Domain of p115RhoGEF*

Zhe ChenDagger §, William D. Singer§, Clark D. Wells||, Stephen R. SprangDagger **Dagger Dagger , and Paul C. Sternweis§§

From the Departments of Dagger  Biochemistry and  Pharmacology and the ** Howard Hughes Medical Institute, the University of Texas Southwestern Medical Center, Dallas, Texas 75390

Structural requirements for function of the Rho GEF (guanine nucleotide exchange factor) regulator of G protein signaling (rgRGS) domains of p115RhoGEF and homologous exchange factors differ from those of the classical RGS domains. An extensive mutagenesis analysis of the p115RhoGEF rgRGS domain was undertaken to determine its functional interface with the Galpha 13 subunit. Results indicate that there is global resemblance between the interaction surface of the rgRGS domain with Galpha 13 and the interactions of RGS4 and RGS9 with their Galpha substrates. However, there are distinct differences in the distribution of functionally critical residues between these structurally similar surfaces and an additional essential requirement for a cluster of negatively charged residues at the N terminus of rgRGS. Lack of sequence conservation within the N terminus may also explain the lack of GTPase-activating protein (GAP) activity in a subset of the rgRGS domains. For all mutations, loss of functional GAP activity is paralleled by decreases in binding to Galpha 13. The same mutations, when placed in the context of the p115RhoGEF molecule, produce deficiencies in GAP activity as observed with the rgRGS domain alone but show no attenuation of the regulation of Rho exchange activity by Galpha 13. This suggests that the rgRGS domain may serve a structural or allosteric role in the regulation of the nucleotide exchange activity of p115RhoGEF on Rho by Galpha 13.

* This work was supported by National Institutes of Health Grants GM31954 (to P. C. S.), DK46371 (to S. R. S.), and GM07062 (to C. D. W.), by the Robert A. Welch foundation (to P. C. S. and S. R. S.), the Alfred and Mabel Gilman chair in molecular pharmacology (to P. C. S.), and the John W. and Rhonda K. Pate professorship in biochemistry (to S. R. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

|| Current address: Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.

Dagger Dagger To whom correspondence may be addressed: Dept. of Biochemistry, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9050. Tel.: 214-648-5008; Fax: 214-648-6336; E-mail: stephen.sprang@utsouthwestern.edu.

§§ To whom correspondence may be addressed: Dept. of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9041. Tel.: 214-648-2835; Fax: 214-648-2971; E-mail: paul.sternweis@utsouthwestern.edu.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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