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J. Biol. Chem., Vol. 278, Issue 49, 49342-49347, December 5, 2003

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Binding of Anthrax Toxin to Its Receptor Is Similar to Integrin-Ligand Interactions^*

Kenneth A. Bradley¶, Jeremy Mogridge||, G. Jonah, A. Rainey**, Sarah Batty||, and John A. T. Young

From the McArdle Laboratory for Cancer Research, University of Wisconsin-Madison, Madison, Wisconsin 53706, and Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90095, and ^||Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

The secreted protein toxin produced by Bacillus anthracis contributes to virulence of this pathogen and can cause many of the symptoms seen during an anthrax infection, including shock and sudden death. The cellbinding component of anthrax toxin, protective antigen, mediates entry of the toxin into cells by first binding directly to the extracellular integrin-like inserted (I) domain of the cellular anthrax toxin receptor, ATR. Here we report that this interaction requires an intact metal ion-dependent adhesion site (MIDAS) in the receptor as well as the presence of specific divalent cations. Also, we demonstrate that the toxin-receptor interaction is critically dependent on the Asp-683 carboxylate group of protective antigen, which projects from the receptor binding surface. We propose that this carboxylate group completes the coordination of the MIDAS metal of ATR, mimicking integrin-ligand interactions.

Received for publication, July 21, 2003 , and in revised form, September 16, 2003.

^* This work was supported in part by Grant AI48489 from the National Institutes of Health (to J. A. T. Y.). Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility, which is supported by National Institutes of Health Awards CA-16042 and AI-28697, by the JCCC, the UCLA AIDS Institute, and the Geffen School of Medicine at UCLA. 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.

^** Supported by Training in Oncology Grant T32 CA09075.

Present address: Infectious Disease Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, 92037.

^¶ To whom correspondence should be addressed: Dept. of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, 609 Charles E. Young Dr. East, Los Angeles, CA 90095. Tel.: 310-206-7465; Fax: 310-206-5231; E-mail: kbradley{at}microbio.ucla.edu.

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