Crystallographic studies of the anthrax lethal toxin. Final report, 1 July 1994-31 December 1996
Protective Antigen (PA) is the central component of the three-part protein toxin secreted by Bacillus anthraces, the organism responsible for anthrax. Following proteolytic activation on the host cell surface, PA forms a membrane-inserting heptamer that translocates the toxic enzymes into the cytosol. We have solved the crystal structure of monomeric PA at 2.1 A resolution and the water-soluble heptamer at 4.5 A resolution. The monomer is organized mainly into antiparallel b-sheets and has four domains: an N-terminal domain containing two calcium ions; a heptamerization domain containing a large flexible loop implicated in membrane insertion; a small domain of unknown function; and a C-terminal receptor-binding domain. Removal of a 20 kDa fragment from the N-terminal domain permits 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 present a model of pH-dependent membrane insertion involving formation of a porin-like membrane-spanning b barrel. These studies greatly enhance current understanding of the mechanism of anthrax intoxication, and will be useful in the design of recombinant anthrax vaccines.
- Research Organization:
- Dana-Farber Cancer Inst., Boston, MA (United States)
- OSTI ID:
- 484705
- Report Number(s):
- AD-A-323011/7/XAB; CNN: Contract DAMD17-94-C-4047; TRN: 71470507
- Resource Relation:
- Other Information: PBD: Jan 1997
- Country of Publication:
- United States
- Language:
- English
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