Proteolytic Inactivation of MAP-Kinase-Kinase by Anthrax Lethal Factor

Author:

Duesbery Nicholas S.12345,Webb Craig P.12345,Leppla Stephen H.12345,Gordon Valery M.12345,Klimpel Kurt R.12345,Copeland Terry D.12345,Ahn Natalie G.12345,Oskarsson Marianne K.12345,Fukasawa Kenji12345,Paull Ken D.12345,Vande Woude George F.12345

Affiliation:

1. N. S. Duesbery, C. P. Webb, T. D. Copeland, M. K. Oskarsson, G. F. Vande Woude, Advanced BioScience Laboratories–Basic Research Program, National Cancer Institute–Frederick Cancer Research and Development Center, Post Office Box B, Frederick, MD 21702, USA.

2. S. H. Leppla, V. M. Gordon, K. R. Klimpel, National Institute of Dental Research–National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.

3. N. G. Ahn, Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of Colorado, Campus Box 215, Boulder, CO 80309, USA.

4. K. Fukasawa, Department of Cell Biology, University of Cincinnati, College of Medicine, P.O. Box 670521, Cincinnati, OH 45267, USA.

5. K. D. Paull, Division of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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