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J. Biol. Chem., Vol. 281, Issue 49, 37942-37951, December 8, 2006

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Structure of FitAB from Neisseria gonorrhoeae Bound to DNA Reveals a Tetramer of Toxin-Antitoxin Heterodimers Containing Pin Domains and Ribbon-Helix-Helix Motifs^*

Kirsten Mattison¹, J. Scott Wilbur, Magdalene So, and Richard G. Brennan²

From the Departments of Biochemistry and Molecular Biology and Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon 97239

Neisseria gonorrhoeae is a sexually transmitted pathogen that initiates infections in humans by adhering to the mucosal epithelium of the urogenital tract. The bacterium then enters the apical region of the cell and traffics across the cell to exit into the subepithelial matrix. Mutations in the fast intracellular trafficking (fitAB) locus cause the bacteria to transit a polarized epithelial monolayer more quickly than the wild-type parent and to replicate within cells at an accelerated rate. Here, we describe the crystal structure of the toxin-antitoxin heterodimer, FitAB, bound to a high affinity 36-bp DNA fragment from the fitAB promoter. FitA, the antitoxin, binds DNA through its ribbon-helix-helix motif and is tethered to FitB, the toxin, to form a heterodimer by the insertion of a four turn -helix into an extensive FitB hydrophobic pocket. FitB is composed of a PIN (PilT N terminus) domain, with a central, twisted, 5-stranded parallel -sheet that is open on one side and flanked by five -helices. FitB in the context of the FitAB complex does not display nuclease activity against tested PIN substrates. The FitAB complex points to the mechanism by which antitoxins with RHH motifs can block the activity of toxins with PIN domains. Interactions between two FitB molecules result in the formation of a tetramer of FitAB heterodimers, which binds to the 36-bp DNA fragment and provides an explanation for how FitB enhances the DNA binding affinity of FitA.

Received for publication, May 31, 2006 , and in revised form, September 11, 2006.

The atomic coordinates and structure factors (code 2H1C and 2H1O) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by National Institutes of Health Grant AI47260 (to M. S.) and funds from the Robert A. Welch Foundation (G-0040). 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 A postdoctoral fellow of the American Heart Association, Pacific Mountain Affiliate. Present address: Bureau of Microbial Hazards, Health Products and Food Branch, Health Canada, Ottawa, ON K1A 0K9, Canada.

² The Robert A. Welch Distinguished University Chair in Chemistry at UT MDACC. To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Texas MD Anderson Cancer Center, Unit 100, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-834-6390; Fax: 713-834-6397; E-mail: rgbrenna{at}mdanderson.org.

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