Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor.
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.
Duesbery
N S
NS
Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Post Office Box B, Frederick, MD 21702.
Webb
C P
CP
Leppla
S H
SH
Gordon
V M
VM
Klimpel
K R
KR
Copeland
T D
TD
Ahn
N G
NG
Oskarsson
M K
MK
Fukasawa
K
K
Paull
K D
KD
Vande Woude
G F
GF
D000818:Animals; D000942:Antigens, Bacterial; D001408:Bacillus anthracis / Q000201:enzymology; D001427:Bacterial Toxins / Q000378:metabolism / Q000633:toxicity*; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002461:Cell Line, Transformed; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000633:toxicity; D006801:Humans; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D008666:Metalloendopeptidases / Q000378:metabolism / Q000633:toxicity; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D004676:Myelin Basic Protein / Q000378:metabolism; D009865:Oocytes / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D014982:Xenopus laevis
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D004676:Myelin Basic Protein; D011993:Recombinant Fusion Proteins; C030325:anthrax toxin; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D008666:Metalloendopeptidases