Send to

Choose Destination
Nat Struct Mol Biol. 2013 Oct;20(10):1182-90. doi: 10.1038/nsmb.2668. Epub 2013 Sep 15.

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

Author information

King's College London British Heart Foundation Centre of Excellence. The Rayne Institute, St Thomas' Hospital Campus, London, SE1 7EH, UK.
Randall Division of Cell and Molecular Biophysics, Guy's Campus, King's College London, London, SE1 1UL, UK.
University of Oxford, Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Oxford OX3 7LD, UK.
Department of Biochemistry and Molecular Biology, George Washington University, Washington, DC 20037, USA.
University of Oxford, Nuffield Department of Clinical Medicine, Target Discovery Institute, Oxford OX3 7FZ, UK.
Contributed equally


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 coexpression 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, allowing autophosphorylation in cis. Interference with p38α recognition by TAB1 abolishes its cardiac toxicity. Such intervention could potentially circumvent the drawbacks of clinical pharmacological inhibitors of p38 catalytic activity.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center