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J. Biol. Chem., Vol. 281, Issue 35, 25365-25372, September 1, 2006

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Differences in Crystal and Solution Structures of the Cytolethal Distending Toxin B Subunit

RELEVANCE TO NUCLEAR TRANSLOCATION AND FUNCTIONAL ACTIVATION^*

From the Division of Cell Biology and Biophysics, School of Biological Sciences, University of Missouri, Kansas City, Missouri 64110-2499

Cytolethal distending toxin (CDT) induces cell cycle arrest and apoptosis in eukaryotic cells, which are mediated by the DNA-damaging CdtB subunit. Here we report the first x-ray structure of an isolated CdtB subunit (Escherichia coli-II CdtB, EcCdtB). In conjunction with previous structural and biochemical observations, active site structural comparisons between free and holotoxin-assembled CdtBs suggested that CDT intoxication is contingent upon holotoxin disassembly. Solution NMR structural and ¹⁵N relaxation studies of free EcCdtB revealed disorder in the interface with the CdtA and CdtC subunits (residues Gly²³³–Asp²⁴²). Residues Leu¹⁸⁶–Thr²⁰⁹ of EcCdtB, which encompasses tandem arginine residues essential for nuclear translocation and intoxication, were also disordered in solution. In stark contrast, nearly identical well defined -helix and -strand secondary structures were observed in this region of the free and holotoxin CdtB crystallographic models, suggesting that distinct changes in structural ordering characterize subunit disassembly and nuclear localization factor binding functions.

Received for publication, April 18, 2006 , and in revised form, June 26, 2006.

^* This work was supported in part by Grant AI 047999 from the United States Public Health Services, NIAID, National Institutes of Health (to L. D.). 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 Figs. 1 and 2.

The atomic coordinates and structure factors (code 2F1N) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ Both authors contributed equally to this work.

² Current address: Dept. of Molecular Biology and Biochemistry, University of Kansas Medical Center, Kansas City, Kansas 66160.

³ To whom correspondence should be addressed: Dept. of Cell Biology and Biophysics, University of Missouri-Kansas City, 5007 Rockhill Rd., 103 BSB, Kansas City, MO 64110. Tel.: 816-235-5345; Fax: 816-235-6584; E-mail: laityj{at}umkc.edu.

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