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J. Biol. Chem., Vol. 282, Issue 18, 13813-13823, May 4, 2007

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Auto-inhibition of the Dbl Family Protein Tim by an N-terminal Helical Motif^*

Marielle E. Yohe, Kent L. Rossman¹, Olivia S. Gardner^¶2, Antoine E. Karnoub², Jason T. Snyder, Svetlana Gershburg, Lee M. Graves, Channing J. Der³, and John Sondek^||4

From the Departments of Pharmacology and ^||Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, ^¶Curriculum in Toxicology, University of North Carolina, Chapel Hill, North Carolina 27599-7295

Dbl-related oncoproteins are guanine nucleotide exchange factors specific for Rho-family GTPases and typically possess tandem Dbl homology (DH) and pleckstrin homology domains that act in concert to catalyze exchange. Because the ability of many Dbl-family proteins to catalyze exchange is constitutively activated by truncations N-terminal to their DH domains, it has been proposed that the activity of Dbl-family proteins is regulated by auto-inhibition. However, the exact mechanisms of regulation of Dbl-family proteins remain poorly understood. Here we show that the Dbl-family protein, Tim, is auto-inhibited by a short, helical motif immediately N-terminal to its DH domain, which directly occludes the catalytic surface of the DH domain to prevent GTPase activation. Similar to the distantly related Vav isozymes, auto-inhibition of Tim is relieved by truncation, mutation, or phosphorylation of the auto-inhibitory helix. A peptide comprising the helical motif inhibits the exchange activity of Tim in vitro. Furthermore, substitutions within the most highly conserved surface of the DH domain designed to disrupt interactions with the auto-inhibitory helix also activate the exchange process.

Received for publication, January 8, 2007 , and in revised form, March 1, 2007.

^* 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 Supported by the American Cancer Society.

² Supported by the Susan G. Komen Breast Cancer Foundation.

³ Supported by National Institutes of Health Grants CA92240 and CA063071.

⁴ Supported by National Institutes of Health Grants GM65533 and GM62299. To whom correspondence should be addressed: CB #7365, 1106 M. E. J. Bldg., Chapel Hill, NC 27599. Tel.: 919-966-7350; E-mail: Sondek{at}med.unc.edu.

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