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Crystal structure of the anthrax toxin protective antigen

Nature volume 385, pages 833–838 (1997)Cite this article

Abstract

Protective antigen (PA) is the central component of the three-part protein toxin secreted by Bacillus anthracis, the organism responsible for anthrax1. After proteolytic activation on the host cell surface, PA forms a membrane-inserting heptamer that translocates the toxic enzymes, oedema factor and lethal factor, into the cytosol2–4. PA, which has a relative molecular mass of 83,000 (Mr 83K), can also translocate heterologous proteins, and is being evaluated for use as a general protein delivery system5,6. Here we report the crystal structure of monomeric PA at 2.1 Å resolution and the water-soluble heptamer at 4.5 Å resolution. The monomer is organized mainly into antiparallel β-sheets and has four domains: an amino-terminal domain (domain 1) containing two calcium ions and the cleavage site for activating proteases; a heptamerization domain (domain 2) containing a large flexible loop implicated in membrane insertion; a small domain of unknown function (domain 3); and a carboxy-terminal receptor-binding domain (domain 4). Removal of a 20K amino-terminal fragment from domain 1 allows the assembly of the heptamer, a ring-shaped structure with a negatively charged lumen, and exposes a large hydrophobic surface for binding the toxic enzymes. We propose a model of pH-dependent membrane insertion involving the formation of a porin-like, membrane-spanning β-barrel.

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Authors and Affiliations

  1. Biochemistry Department, University of Leicester, Leicester, LE1 7RH, UK

    Carlo Petosa & Robert C. Liddington

  2. Department of Microbiology & Molecular Genetics, 200 Longwood Avenue, Harvard Medical School, Boston, Massachusetts, 02115, USA

    R. John Collier

  3. Laboratory of Microbial Ecology, Building 30, Room 309, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland, 20982, USA

    Kurt R. Klimpel & Stephen H. Leppla

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  1. Carlo Petosa
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  2. R. John Collier
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  4. Stephen H. Leppla
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  5. Robert C. Liddington
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Petosa, C., Collier, R., Klimpel, K. et al. Crystal structure of the anthrax toxin protective antigen. Nature 385, 833–838 (1997). https://doi.org/10.1038/385833a0

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