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J. Biol. Chem., Vol. 280, Issue 23, 21779-21784, June 10, 2005

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Mechanism of Transcription Factor Recruitment by Acidic Activators^*

Monica E. Ferreira¶, Stefan Hermann, Philippe Prochasson||**, Jerry L. Workman||, Kurt D. Berndt, and Anthony P. H. Wright

From the Department of Life Sciences, Södertörns Högskola, S-141 89 Huddinge, Sweden, Department of Biosciences, Karolinska Institutet, NOVUM, S-141 57 Huddinge, Sweden, and ^||Stowers Institute for Medical Research, Kansas City, Missouri 64110

Many transcriptional activators are intrinsically unstructured yet display unique, defined conformations when bound to target proteins. Target-induced folding provides a mechanism by which activators could form specific interactions with an array of structurally unrelated target proteins. Evidence for such a binding mechanism has been reported previously in the context of the interaction between the cancer-related c-Myc protein and the TATA-binding protein, which can be modeled as a two-step process in which a rapidly forming, low affinity complex slowly converts to a more stable form, consistent with a coupled binding and folding reaction. To test the generality of the target-induced folding model, we investigated the binding of two widely studied acidic activators, Gal4 and VP16, to a set of target proteins, including TATA-binding protein and the Swi1 and Snf5 subunits of the Swi/Snf chromatin remodeling complex. Using surface plasmon resonance, we show that these activator-target combinations also display bi-phasic kinetics suggesting two distinct steps. A fast initial binding phase that is inhibited by high ionic strength is followed by a slow phase that is favored by increased temperature. In all cases, overall affinity increases with temperature and, in most cases, with increased ionic strength. These results are consistent with a general mechanism for recruitment of transcriptional components to promoters by naturally occurring acidic activators, by which the initial contact is mediated predominantly through electrostatic interactions, whereas subsequent target-induced folding of the activator results in a stable complex.

Received for publication, March 9, 2005 , and in revised form, April 11, 2005.

^* This work was supported in part by project grants from the Swedish Research Council. 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.

^** A fellow of the Leukemia and Lymphoma Society.

A senior investigator supported by the Swedish Research Council.

^¶ To whom correspondence should be addressed. Tel.: 46-8-608-4716; Fax: 46-8-608-4510; E-mail: monica.ferreira{at}sh.se.

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