Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor

N S Duesbery; C P Webb; S H Leppla; V M Gordon; K R Klimpel; T D Copeland; N G Ahn; M K Oskarsson; K Fukasawa; K D Paull; G F Vande Woude

doi:10.1126/science.280.5364.734

Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor

Science. 1998 May 1;280(5364):734-7. doi: 10.1126/science.280.5364.734.

Authors

N S Duesbery¹, C P Webb, S H Leppla, V M Gordon, K R Klimpel, T D Copeland, N G Ahn, M K Oskarsson, K Fukasawa, K D Paull, G F Vande Woude

Affiliation

¹ Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Post Office Box B, Frederick, MD 21702.

PMID: 9563949
DOI: 10.1126/science.280.5364.734

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.

Publication types

Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Antigens, Bacterial*
Bacillus anthracis* / enzymology
Bacterial Toxins / metabolism
Bacterial Toxins / toxicity*
Binding Sites
Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
Calcium-Calmodulin-Dependent Protein Kinases / metabolism
Cell Line, Transformed
Enzyme Activation
Enzyme Inhibitors / toxicity
Humans
MAP Kinase Kinase 1
MAP Kinase Kinase 2
Metalloendopeptidases / metabolism
Metalloendopeptidases / toxicity
Mice
Mitogen-Activated Protein Kinase Kinases*
Myelin Basic Protein / metabolism
Oocytes / physiology
Phosphorylation
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / chemistry
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism
Recombinant Fusion Proteins / metabolism
Sequence Deletion
Signal Transduction
Xenopus laevis

Substances

Antigens, Bacterial
Bacterial Toxins
Enzyme Inhibitors
Myelin Basic Protein
Recombinant Fusion Proteins
anthrax toxin
MAP2K2 protein, human
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases
Calcium-Calmodulin-Dependent Protein Kinases
MAP Kinase Kinase 1
MAP Kinase Kinase 2
MAP2K1 protein, human
Map2k1 protein, mouse
Mitogen-Activated Protein Kinase Kinases
Metalloendopeptidases