Proteolytic Inactivation of MAP-Kinase-Kinase by Anthrax Lethal Factor
Nicholas S. Duesbery(Howard Hughes Medical Institute), Craig P. Webb(Howard Hughes Medical Institute), Stephen H. Leppla(Howard Hughes Medical Institute), V M Gordon(Howard Hughes Medical Institute), Kurt R. Klimpel(Howard Hughes Medical Institute), Terry D. Copeland(Howard Hughes Medical Institute), Natalie G. Ahn(Howard Hughes Medical Institute), Marianne Oskarsson(Howard Hughes Medical Institute), Kenji Fukasawa(Howard Hughes Medical Institute), K Paull(Howard Hughes Medical Institute), George F. Vande Woude(Howard Hughes Medical Institute)
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Abstract
Anthrax lethal toxin, produced by the bacterium Bacillus anthracis, is the major cause of death in animals infected with anthrax. One component of this toxin, lethal factor (LF), is suspected to be a metalloprotease, but no physiological substrates have been identified. Here it is shown that LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and MAPKK2) and that this cleavage inactivates MAPKK1 and inhibits the MAPK signal transduction pathway. The identification of a cleavage site for LF may facilitate the development of LF inhibitors.
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