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Originally published In Press as doi:10.1074/jbc.M008309200 on December 11, 2000

J. Biol. Chem., Vol. 276, Issue 11, 8371-8376, March 16, 2001
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Point Mutations in Anthrax Protective Antigen That Block Translocation*

Bret R. SellmanDagger , Shilla Nassi§, and R. John CollierDagger

From the Dagger  Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115 and the § Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

The protective antigen (PA) moiety of anthrax toxin delivers the toxin's enzymatic moieties to the cytosol of mammalian cells by a mechanism associated with its ability to heptamerize and form a transmembrane pore. Here we report that mutations in Lys-397, Asp-425, or Phe-427 ablate killing of CHO-K1 cells by a cytotoxic PA ligand. These mutations blocked PA's ability to mediate pore formation and translocation in cells but had no effect on its receptor binding, proteolytic activation, or ability to oligomerize and bind the toxin's enzymatic moieties. The mutation-sensitive residues lie in the 2beta 7-2beta 8 and 2beta 10-2beta 11 loops of domain 2 and are distant both in primary structure and topography from the 2beta 2-2beta 3 loop, which is believed to participate in formation of a transmembrane beta -barrel. These results suggest that Lys-397, Asp-425, and Phe-427 participate in conformational rearrangements of a heptameric pore precursor that are necessary for pore formation and translocation. Identification of these residues will aid in elucidating the mechanism of translocation and may be useful in developing therapeutic and prophylactic agents against anthrax.

* This work was supported by National Institutes of Health Grants R37-AI22021 (to R. J. C.), T-32-GM-07288 (to S. N.), and GM-29210 (to Alan Finkelstein).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Has financial interest in AVANT Immunotherapeutics, Inc. To whom correspondence should be addressed: Tel.: 617-432-1930; Fax: 617-432-0115; E-mail: jcollier@hms.harvard.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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