Anthrax lethal factor-cleavage products of MAPK (mitogen-activated protein kinase) kinases exhibit reduced binding to their cognate MAPKs
Anthrax lethal factor-cleavage products of MAPK (mitogen-activated protein kinase) kinases exhibit reduced binding to their cognate MAPKs
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DOI：
10.1042/bj20031382
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发表时间：
2004-03-01
影响因子：
4.1
通讯作者：
Bardwell, L
中科院分区：
文献类型：
--
作者：
Bardwell, AJ;Abdollahi, M;Bardwell, L
炭疽致死毒素是系统性炭疽病的主要致死原因。致死毒素由保护性抗原和致死因子两种蛋白质组成。保护性抗原与细胞表面受体结合，并将LF运送到胞浆中。Lf是一种针对MKKs[MAPK(丝裂原活化蛋白激酶)激酶]/MEKs[MAPK/ERK(细胞外信号调节激酶)激酶]的金属蛋白酶，将它们裂解以移除一小段N末端延伸，但保持大部分蛋白质，包括蛋白激酶结构域不变。LF介导的MEK1和MKK6的切割已被证明通过其同源的MAPK通路抑制信号传导。然而，这种蛋白水解性切割抑制信号传递的确切机制还不清楚。在这里，我们发现MEK1，MEK2，MKK3，MKK4，MKK6和MKK7的C末端LF裂解产物与其MAPK底物结合的能力受到损害，这表明了LF诱导信号抑制的共同机制。
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.