Anthrax toxin.
Anthrax toxin consists of three nontoxic proteins that associate in binary or ternary combinations to form toxic complexes at the surface of mammalian cells. One of these proteins, protective antigen (PA), transports the other two, edema factor (EF) and lethal factor (LF), to the cytosol. LF is a Zn2+-protease that cleaves certain MAP kinase kinases, leading to death of the host via a poorly defined sequence of events. EF, a calmodulin- and Ca2+-dependent adenylate cyclase, is responsible for the edema seen in the disease. Both enzymes are believed to benefit the bacteria by inhibiting cells of the host's innate immune system. Assembly of toxic complexes begins after PA binds to cellular receptors and is cleaved into two fragments by furin proteases. The smaller fragment dissociates, allowing the receptor-bound fragment, PA63 (63 kDa), to self-associate and form a ring-shaped, heptameric pore precursor (prepore). The prepore binds up to three molecules of EF and/or LF, and the resulting complexes are endocytosed and trafficked to an acidic compartment. There, the prepore converts to a transmembrane pore, mediating translocation of EF and LF to the cytosol. Recent studies have revealed (a) the identity of receptors; (b) crystallographic structures of the three toxin proteins and the heptameric PA63 prepore; and (c) information about toxin assembly, entry, and action within the cytosol. Knowledge of the structure and mode of action of the toxin has unveiled potential applications in medicine, including approaches to treating anthrax infections.
Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. jcollier@hms.harvard.edu
R John
RJ
Collier
John A T
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Young
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D000881:Anthrax / Q000201:enzymology / Q000503:physiopathology; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D046911:Macromolecular Substances; D008958:Models, Molecular; D021381:Protein Transport / Q000502:physiology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002352:Carrier Proteins; D046911:Macromolecular Substances; D011956:Receptors, Cell Surface; C030325:anthrax toxin; D000262:Adenylyl Cyclases