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J. Biol. Chem., Vol. 281, Issue 43, 32891-32897, October 27, 2006

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The Molecular Basis of RhoA Specificity in the Guanine Nucleotide Exchange Factor PDZ-RhoGEF^*

Arkadiusz Oleksy, L/ukasz Opaliski, Urszula Derewenda, Zygmunt S. Derewenda, and Jacek Otlewski¹

From the Institute of Biochemistry and Molecular Biology, University of Wroclaw, 50-137 Wroclaw, Poland and the Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, Virginia 22908

The Dbl homology nucleotide exchange factors (GEFs) activate Rho family cytosolic GTPases in a variety of physiological and pathophysiological events. These signaling molecules typically act downstream of tyrosine kinase receptors and often facilitate nucleotide exchange on more than one member of the Rho GTPase superfamily. Three unique GEFs, i.e. p115, PDZ-RhoGEF, and LARG, are activated by the G-protein coupled receptors via the G_12/13, and exhibit very selective activation of RhoA, although the mechanism by which this is accomplished is not fully understood. Based on the recently solved crystal structure of the DH-PH tandem of PDZ-RhoGEF in complex with RhoA (Derewenda, U., Oleksy, A., Stevenson, A. S., Korczynska, J., Dauter, Z., Somlyo, A. P., Otlewski, J., Somlyo, A. V., and Derewenda, Z. S. (2004) Structure (Lond.) 12, 1955-1965), we conducted extensive mutational and functional studies of the molecular basis of the RhoA selectivity in PDZ-RhoGEF. We show that while Trp⁵⁸ of RhoA is intimately involved in the interaction with the DH domain, it is not a selectivity determinant, and its interaction with PDZ-RhoGEF is unfavorable. The key selectivity determinants are dominated by polar contacts involving residues unique to RhoA. We find that selectivity for RhoA versus Cdc42 is defined by a small number of interactions.

Received for publication, June 29, 2006 , and in revised form, August 16, 2006.

^* This work was supported in part by National Institutes of Health Grant PO1 HL48807 (to Z. S. D.), by Polish Ministry of Science and Higher Education Grant 2P04A05626 (to J. O.), and by a NATO Collaborative Linkage Grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 48-71-375-28-24; Fax: 48-71-375-26-08; E-mail: otlewski{at}protein.pl.

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