Anthrax lethal factor-cleavage products of MAPK (mitogen-activated protein kinase) kinases exhibit reduced binding to their cognate MAPKs.
Anthrax lethal toxin is the major cause of death in systemic anthrax. Lethal toxin consists of two proteins: protective antigen and LF (lethal factor). Protective antigen binds to a cell-surface receptor and transports LF into the cytosol. LF is a metalloprotease that targets MKKs [MAPK (mitogen-activated protein kinase) kinases]/MEKs [MAPK/ERK (extracellular-signal-regulated kinase) kinases], cleaving them to remove a small N-terminal stretch but leaving the bulk of the protein, including the protein kinase domain, intact. LF-mediated cleavage of MEK1 and MKK6 has been shown to inhibit signalling through their cognate MAPK pathways. However, the precise mechanism by which this proteolytic cleavage inhibits signal transmission has been unclear. Here we show that the C-terminal LF-cleavage products of MEK1, MEK2, MKK3, MKK4, MKK6 and MKK7 are impaired in their ability to bind to their MAPK substrates, suggesting a common mechanism for the LF-induced inhibition of signalling.
Bardwell
A Jane
AJ
Department of Developmental and Cell Biology, 2208 Natural Sciences I, University of California, Irvine, CA 92697, U.S.A.
Abdollahi
Mahsa
M
Bardwell
Lee
L
D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000737:chemistry / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D016415:Sequence Alignment; D048051:p38 Mitogen-Activated Protein Kinases
D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin; C482128:MAP2K2 protein, human; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D048371:MAP Kinase Kinase 3; D048670:MAP Kinase Kinase 4; D048669:MAP Kinase Kinase 6; D048688:MAP Kinase Kinase 7; C482125:MAP2K1 protein, human; C482530:MAP2K3 protein, human; C482559:MAP2K4 protein, human; C482566:MAP2K6 protein, human; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases