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J. Biol. Chem., Vol. 281, Issue 27, 18774-18786, July 7, 2006

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Regulation of RhoGEF Activity by Intramolecular and Intermolecular SH3 Domain Interactions^*

Martin R. Schiller^¶1, Kausik Chakrabarti, Glenn F. King, Noraisha I. Schiller, Betty A. Eipper, and Mark W. Maciejewski

From the Departments of Neuroscience and Molecular, Microbial, and Structural Biology and the ^¶Center for Structural Biology, University of Connecticut Health Center, Farmington, Connecticut 06019-4301

RhoGEFs are central controllers of small G-proteins in cells and are regulated by several mechanisms. There are at least 22 human RhoGEFs that contain SH3 domains, raising the possibility that, like several other enzymes, SH3 domains control the enzymatic activity of guanine nucleotide exchange factor (GEF) domains through intra- and/or intermolecular interactions. The structure of the N-terminal SH3 domain of Kalirin was solved using NMR spectroscopy, and it folds much like other SH3 domains. However, NMR chemical shift mapping experiments showed that this Kalirin SH3 domain is unique, containing novel cooperative binding site(s) for intramolecular PXXP ligands. Intramolecular Kalirin SH3 domain/ligand interactions, as well as binding of the Kalirin SH3 domain to the adaptor protein Crk, inhibit the GEF activity of Kalirin. This study establishes a novel molecular mechanism whereby intramolecular and intermolecular Kalirin SH3 domain/ligand interactions modulate GEF activity, a regulatory mechanism that is likely used by other RhoGEF family members.

Received for publication, November 21, 2005 , and in revised form, April 24, 2006.

The atomic coordinates and structure factors (code 1U3O) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The chemical shifts have been deposited in the Biological Magnetic Resonance Data Bank under BMRB accession number 6300 (www.bmrb.wisc.edu/).

^* This work was supported by National Institutes of Health Grants MH65567 and DK32948 and by a University of Connecticut Health Center faculty development award (to M. R. S.). 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: Dept. of Neuroscience, University of Connecticut Health Center, 263 Farmington Ave., Farmington, CT 06019-4301. Tel.: 860-679-4610; Fax: 860-679-1726; E-mail: schiller{at}nso.uchc.edu.

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