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J. Biol. Chem., Vol. 280, Issue 33, 29689-29698, August 19, 2005

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Unraveling the Mechanism of a Potent Transcriptional Activator^*

Zhen Lu, Steven P. Rowe¶||, Brian B. Brennan¶, Sarah E. Davis, Renee E. Metzler, Johnathan J. Nau, Chinmay Y. Majmudar¶, Anna K. Mapp, Supported by National Institutes of Health Grant GM65330, the Burroughs Wellcome Fund, and the March of Dimes¶**, and Aseem Z. Ansari, Supported by the March of Dimes Foundation, the Steenback Career Development Award, and Industrial and Economic Development Research funds from University of Wisconsin-Madison and Wisconsin Alumni Research Foundation

From the Department of Biochemistry and The Genome Center, University of Wisconsin, Madison, Wisconsin 53706 and the ^¶Department of Chemistry and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109

Despite their enormous potential as novel research tools and therapeutic agents, artificial transcription factors (ATFs) that up-regulate transcription robustly in vivo remain elusive. In investigating an ATF that does function exceptionally well in vivo, we uncovered an unexpected relationship between transcription function and a binding interaction between the activation domain and an adjacent region of the DNA binding domain. Disruption of this interaction leads to complete loss of function in vivo, even though the activation domain is still able to bind to its target in the transcriptional machinery. We propose that this interaction parallels those between natural activation domains and their regulatory proteins, concealing the activation domain from solvent and the cellular milieu until it binds to its transcriptional machinery target. Inclusion of this property in the future design of ATFs should enhance their efficacy in vivo.

Received for publication, May 4, 2005

^* 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.

The on-line version of this article (available at http://www.jbc.org) contains Figs. 1-3.

These authors contributed equally to this work.

^|| Supported by National Institutes of Health Grant GM07863 and NASA Graduate Research Fellowship F008372.

^** To whom correspondence may be addressed: Dept. of Chemistry, University of Michigan, Ann Arbor, MI 48109. E-mail: amapp{at}umich.edu. To whom correspondence may be addressed: Dept. of Biochemistry, 433 Babcock Dr., University of Wisconsin, Madison, WI 53706. Tel.: 608-265-4690; Fax: 608-262-3453; E-mail: ansari{at}biochem.wisc.edu.

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