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J. Biol. Chem., Vol. 283, Issue 27, 18646-18654, July 4, 2008

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Deoxycholate Interacts with IpaD of Shigella flexneri in Inducing the Recruitment of IpaB to the Type III Secretion Apparatus Needle Tip^*

Kenneth F. Stensrud¹, Philip R. Adam¹, Cassandra D. La Mar, Andrew J. Olive², Gerald H. Lushington, Raghavi Sudharsan, Naomi L. Shelton, Richard S. Givens, Wendy L. Picking, and William D. Picking³

From the Departments of Molecular Biosciences and Chemistry, University of Kansas, Lawrence, Kansas 66045

Type III secretion (TTS) is an essential virulence function for Shigella flexneri that delivers effector proteins that are responsible for bacterial invasion of intestinal epithelial cells. The Shigella TTS apparatus (TTSA) consists of a basal body that spans the bacterial inner and outer membranes and a needle exposed at the pathogen surface. At the distal end of the needle is a "tip complex" composed of invasion plasmid antigen D (IpaD). IpaD not only regulates TTS, but is required for the recruitment and stable association of the translocator protein IpaB at the TTSA needle tip in the presence of deoxycholate or other bile salts. This phenomenon is not accompanied by induction of TTS or the recruitment of IpaC to the Shigella surface. We now show that IpaD specifically binds fluorescein-labeled deoxycholate and, based on energy transfer measurements and docking simulations, this interaction appears to occur where the N-terminal domain of IpaD meets its central coiled-coil, a region that may also be involved in needle-tip interactions. TTS is initiated as a series of distinct steps and that small molecules present in the bacterial milieu are capable of inducing the first step of TSS through interactions with the needle tip protein IpaD. Furthermore, the amino acids proposed to be important for deoxycholate binding by IpaD appear to have significant roles in regulating tip complex composition and pathogen entry into host cells.

Received for publication, April 11, 2008 , and in revised form, April 24, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants P20 RR016475 awarded to the Kansas IDeA Network of Biomedical Research Excellence (K-INBRE) (to P. R. A.) and R25GM62232 awarded to the Initiative for Maximizing Student Diversity (IMSD) (to C. D. L.). This work was also supported by United States Public Health Service Grants AI034428 (to W. D. P.), AI067858 and AI072510 (to W. L. P.), and R01 GM72910 (to R. S. G.). 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 Scheme 1, Materials, Figs. S1 and S2, and Table S1.

¹ Both authors contributed equally to this work.

² Current address: Dept. of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115.

³ To whom correspondence should be addressed: 1200 Sunnyside Ave., Lawrence, KS 66045-7534. Tel.: 785-864-3299; Fax: 785-864-5294; E-mail: picking{at}ku.edu.

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