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J. Biol. Chem., Vol. 280, Issue 14, 13779-13783, April 8, 2005

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Crystal Structure of the Virulence Gene Activator AphA from Vibrio cholerae Reveals It Is a Novel Member of the Winged Helix Transcription Factor Superfamily^*

Rukman S. De Silva, Gabriela Kovacikova, Wei Lin, Ronald K. Taylor, Karen Skorupski, and F. Jon Kull¶

From the Department of Chemistry, Dartmouth College and Department of Microbiology and Immunology, Dartmouth Medical School, Hanover, New Hampshire 03755

AphA is a member of a new and largely uncharacterized family of transcriptional activators that is required for initiating virulence gene expression in Vibrio cholerae, the causative agent of the frequently fatal epidemic diarrheal disease cholera. AphA activates transcription by an unusual mechanism that appears to involve a direct interaction with the LysR-type regulator AphB at the tcpPH promoter. As a first step toward understanding the molecular basis for tcpPH activation by AphA and AphB, we have determined the crystal structure of AphA to 2.2 Å resolution. AphA is a dimer with an N-terminal winged helix DNA binding domain that is architecturally similar to that of the MarR family of transcriptional regulators. Unlike this family, however, AphA has a unique C-terminal antiparallel coiled coil domain that serves as its primary dimerization interface. AphA monomers are highly unstable by themselves and form a linked topology, requiring the protein to partially unfold to form the dimer. The structure of AphA also provides insights into how it cooperates with AphB to activate transcription, most likely by forming a heterotetrameric complex at the tcpPH promoter.

Received for publication, December 7, 2004

^* This work was supported by National Institutes of Health Grants AI060031 (to F. J. K.), AI41558 (to K. S.), and AI39654 (to R. K. T.). 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 atomic coordinates and structure factors (code 1YG2) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^¶ To whom correspondence should be addressed: Dept. of Chemistry, 6128 Burke Laboratory, Dartmouth College, Hanover, NH, 03755. Tel.: 603-646-1552; Fax: 603-646-3946; E-mail: f.jon.kull{at}dartmouth.edu.

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