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J. Biol. Chem., Vol. 283, Issue 37, 25752-25764, September 12, 2008

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Weak Organic Acids Trigger Conformational Changes of the Yeast Transcription Factor War1 in Vivo to Elicit Stress Adaptation^*

Christa Gregori, Christoph Schüller¹, Ingrid E. Frohner, Gustav Ammerer, and Karl Kuchler²

From the Medical University of Vienna, Max F. Perutz Laboratories and University of Vienna, Max F. Perutz Laboratories, A-1030 Vienna, Austria

The Saccharomyces cerevisiae zinc cluster regulator War1 mediates an essential transcriptional and adaptive response to weak organic acid stress. Here we investigate the mechanism of War1 activation upon weak acid stress. We identified several gain-of-function WAR1 alleles mapping to the central War1 region. These mutations constitutively increase levels of the plasma membrane ABC transporter Pdr12, the main War1 target mediating stress adaptation. Functional analysis of War1 reveals that the central region and its C-terminal activation domain are required for function. Notably, the native DNA-binding and dimerization domains appear dispensable for War1 activity, because they can be replaced by a LexA DNA-binding domain. Chromatin immunoprecipitation demonstrates elevated promoter affinity of activated War1, because its PDR12 promoter association increases upon stress. Hyperactive WAR1 alleles have constitutively high PDR12 promoter association. Furthermore, fluorescence resonance energy transfer of functional CFP-War1-YFP proteins also demonstrates conformational changes of stress-activated War1 in vivo. Our results suggest a mechanism whereby War1 activation is accompanied by conformational changes enhancing promoter association, thus initiating the adaptation process.

Received for publication, April 22, 2008 , and in revised form, July 1, 2008.

^* This work was supported in part by Austrian Science Foundation Grant P-15934-B08 and in part by Grant SFB35-04 (to K. K.) and by Vienna Biocenter Ph.D. program grant (to I. F.). 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 supplemental Table 5.

¹ Recipient of support through the Herzfelder Family Foundation and the Austrian Science Foundation Grant P-19966-B12. To whom correspondence may be addressed. Tel.: 43-1-4277-52815; Fax: 43-1-4277-9528; E-mail: Christoph.Schueller{at}univie.ac.at.

² To whom correspondence may be addressed. Tel.: 43-1-4277-61807; Fax: 43-1-4277-9618; E-mail: karl.kuchler{at}meduniwien.ac.at.

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