Mechanism and consequence of the autoactivation of p38α mitogen-activated protein kinase promoted by TAB1.
Mechanism and consequence of the autoactivation of p38α mitogen-activated protein kinase promoted by TAB1.
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DOI：
10.1038/nsmb.2668
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发表时间：
2013-10
影响因子：
16.8
通讯作者：
Marber, Michael S.
中科院分区：
文献类型：
--
作者：
De Nicola, Gian Felice;Martin, Eva Denise;Chaikuad, Apirat;Bassi, Rekha;Clark, James;Martino, Luigi;Verma, Sharwari;Sicard, Pierre;Tata, Renee;Atkinson, R. Andrew;Knapp, Stefan;Conte, Maria R.;Marber, Michael S.
p38α丝裂原活化蛋白激酶（Mitogen-activated Protein Kinase，p38α）在心肌缺血和其他应激时通过多种机制被激活，包括由TGFβ激活的激酶1结合蛋白1（TGFβ-activated kinase 1 binding protein 1，TAB 1）启动的自磷酸化。化学遗传学方法和在哺乳动物、细菌和无细胞系统中的共表达揭示，小鼠p38α自身磷酸化通过与TAB 1直接相互作用顺式发生（371-416）。在分离的大鼠心肌细胞和灌注的小鼠心脏中，TAT-TAB 1（371-416）迅速激活p38并严重干扰功能。晶体结构和溶液中的表征揭示了TAB 1在p38α C-末端激酶叶中的二分对接位点。TAB 1结合稳定活性p38α，并通过Thr-Gly-Tyr基序的螺旋延伸诱导激活片段内的重排，从而允许顺式自磷酸化。TAB 1对p38α识别的干扰消除了其心脏毒性。潜在地，这种干预可以规避p38催化活性的药理学抑制剂在临床上使用时所看到的缺点。
p38α Mitogen-activated Protein Kinase (p38α) is activated by a variety of mechanisms, including autophosphorylation initiated by TGFβ-activated kinase 1 binding protein 1 (TAB1) during myocardial ischemia and other stresses. Chemical genetic approaches and co-expression in mammalian, bacterial and cell-free systems revealed that mouse p38α autophosphorylation occurs in cis by direct interaction with TAB1(371-416). In isolated rat cardiac myocytes and perfused mouse hearts TAT-TAB1(371-416) rapidly activates p38 and profoundly perturbs function. Crystal structures and characterization in solution revealed a bipartite docking site for TAB1 in the p38α C-terminal kinase lobe. TAB1 binding stabilizes active p38α and induces rearrangements within the activation segment by helical extension of the Thr-Gly-Tyr motif that allows auto-phosphorylation in cis. Interference with p38α recognition by TAB1 abolishes its cardiac toxicity. Potentially, such intervention could circumvent the drawbacks seen when pharmacological inhibitors of p38 catalytic activity are used clinically.
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影响因子：
56.9
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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