Accession Number : ADA323011
Title : Crystallographic Studies of the Anthrax Lethal Toxin.
Descriptive Note : Final rept. 1 Jul 94-31 Dec 96,
Corporate Author : DANA-FARBER CANCER INST BOSTON MA
Personal Author(s) : Frederick, Christin A.
PDF Url : ADA323011
Report Date : JAN 1997
Pagination or Media Count : 29
Abstract : 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.
Descriptors : *TOXICITY, *LETHALITY, *ANTHRAX, *CRYSTALLOGRAPHY, *HOSTS(BIOLOGY), *BACILLUS ANTHRACIS, IONS, CALCIUM, CRYSTAL STRUCTURE, ENZYMES, CELLS(BIOLOGY), LOOPS, ANTIGENS, HYDROPHOBIC PROPERTIES, VACCINES, BACTERIAL TOXINS, INTOXICATION.
Subject Categories : Medicine and Medical Research
Distribution Statement : APPROVED FOR PUBLIC RELEASE