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J. Biol. Chem., Vol. 282, Issue 6, 4035-4044, February 9, 2007

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Self-chaperoning of the Type III Secretion System Needle Tip Proteins IpaD and BipD^*

Steven Johnson¹², Pietro Roversi¹³, Marianela Espina^¶, Andrew Olive^¶, Janet E. Deane⁴, Susan Birket^¶, Terry Field^||, William D. Picking^¶5, Ariel J. Blocker⁶, Edouard E. Galyov^||, Wendy L. Picking^¶, and Susan M. Lea⁷

From the Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, Oxon OX1 3QU, United Kingdom, the Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, United Kingdom, the ^¶Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045, and the ^||Division of Microbiology, Institute for Animal Health, Compton Laboratory, Berkshire RG20 7NN, United Kingdom

Bacteria expressing type III secretion systems (T3SS) have been responsible for the deaths of millions worldwide, acting as key virulence elements in diseases ranging from plague to typhoid fever. The T3SS is composed of a basal body, which traverses both bacterial membranes, and an external needle through which effector proteins are secreted. We report multiple crystal structures of two proteins that sit at the tip of the needle and are essential for virulence: IpaD from Shigella flexneri and BipD from Burkholderia pseudomallei. The structures reveal that the N-terminal domains of the molecules are intramolecular chaperones that prevent premature oligomerization, as well as sharing structural homology with proteins involved in eukaryotic actin rearrangement. Crystal packing has allowed us to construct a model for the tip complex that is supported by mutations designed using the structure.

Received for publication, August 18, 2006 , and in revised form, October 18, 2006.

The atomic coordinates and structure factors (code 2j0o, 2j0n, 2j9t, 2ixr, and 2jaa) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* The work at the Institute for Animal Health was supported in part by the Biotechnology and Biological Sciences Research Council (United Kingdom). 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 and Table 1.

¹ These authors contributed equally to this work.

² Supported by Medical Research Council of the United Kingdom Grant G0400389 (to S. M. L.) and previously by a Guy G. F. Newton Senior Research Fellowship (to A. J. B.).

³ Supported by a Wellcome Trust Grant (No. 077082) (to S. M. L. and P. R.).

⁴ Supported by an Australian National Health and Medical Research Council CJ Martin Postdoctoral Fellowship (ID-358785).

⁵ Supported by Public Health Service Grants AI034428 and RR017708 and by the University of Kansas Research Development Fund.

⁶ Supported by a Guy G. F. Newton Senior Research Fellowship.

⁷ To whom correspondence should be addressed. E-mail: susan.lea{at}path.ox.ac.uk.

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