Mechanism and consequence of the autoactivation of p38α mitogen-activated protein kinase promoted by TAB1

被引:89
作者
De Nicola, Gian Felice [1 ,2 ]
Martin, Eva Denise [1 ]
Chaikuad, Apirat [3 ]
Bassi, Rekha [1 ]
Clark, James [1 ]
Martino, Luigi [2 ]
Verma, Sharwari [1 ]
Sicard, Pierre [1 ]
Tata, Renee [2 ]
Atkinson, R. Andrew [2 ]
Knapp, Stefan [3 ,4 ,5 ]
Conte, Maria R. [2 ]
Marber, Michael S. [1 ]
机构
[1] Kings Coll London, British Heart Fdn Ctr Excellence, Rayne Inst, London, England
[2] Kings Coll London, Randall Div Cell & Mol Biophys, London, England
[3] Univ Oxford, Nuffield Dept Clin Med, Struct Genom Consortium, Oxford, England
[4] George Washington Univ, Dept Biochem & Mol Biol, Washington, DC USA
[5] Univ Oxford, Nuffield Dept Clin Med, Target Discovery Inst, Oxford, England
基金
英国惠康基金; 加拿大创新基金会; 英国医学研究理事会;
关键词
INDEPENDENT ACTIVATION; MAPK ACTIVATION; P38; MAPK; NMR; AUTOPHOSPHORYLATION; APOPTOSIS; BINDING; NUCLEOTIDE; EXPRESSION; SCAFFOLD;
D O I
10.1038/nsmb.2668
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
p38 alpha mitogen-activated protein kinase (p38 alpha) is activated by a variety of mechanisms, including autophosphorylation initiated by TGF beta-activated kinase 1 binding protein 1 (TAB1) during myocardial ischemia and other stresses. Chemical-genetic approaches and coexpression in mammalian, bacterial and cell-free systems revealed that mouse p38 alpha 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 p38 alpha C-terminal kinase lobe. TAB1 binding stabilizes active p38 alpha and induces rearrangements within the activation segment by helical extension of the Thr-Gly-Tyr motif, allowing autophosphorylation in cis. Interference with p38 alpha recognition by TAB1 abolishes its cardiac toxicity. Such intervention could potentially circumvent the drawbacks of clinical pharmacological inhibitors of p38 catalytic activity.
引用
收藏
页码:1182 / +
页数:11
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