Crystal structure of the anthrax toxin protective antigen

Carlo Petosa, R. John Collier, Kurt R. Klimpel, Stephen H. Leppla and Robert C. Liddington
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Carlo Petosa: University of Leicester
R. John Collier: Harvard Medical School
Kurt R. Klimpel: National Institutes of Health
Stephen H. Leppla: National Institutes of Health
Robert C. Liddington: University of Leicester

Nature, 1997, vol. 385, issue 6619, 833-838

Abstract: 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.

Date: 1997
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DOI: 10.1038/385833a0

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