title: Mechanism and consequence of the autoactivation of p38α mitogen-activated protein kinase promoted by TAB1.
abstract: 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.
authors.affiliation: 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.
authors.forename: Gian Felice
authors.initials: GF
authors.lastname: DeNicola
authors.affiliation: King's College London British Heart Foundation Centre of Excellence. The Rayne Institute, St Thomas' Hospital Campus, London, SE1 7EH, UK.
authors.forename: Eva Denise
authors.initials: ED
authors.lastname: Martin
authors.affiliation: University of Oxford, Nuffield Department of Clinical Medicine, Structural Genomics Consortium, Oxford OX3 7LD, UK.
authors.forename: Apirat
authors.initials: A
authors.lastname: Chaikuad
authors.affiliation: King's College London British Heart Foundation Centre of Excellence. The Rayne Institute, St Thomas' Hospital Campus, London, SE1 7EH, UK.
authors.forename: Rekha
authors.initials: R
authors.lastname: Bassi
authors.affiliation: King's College London British Heart Foundation Centre of Excellence. The Rayne Institute, St Thomas' Hospital Campus, London, SE1 7EH, UK.
authors.forename: James
authors.initials: J
authors.lastname: Clark
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Guy's Campus, King's College London, London, SE1 1UL, UK.
authors.forename: Luigi
authors.initials: L
authors.lastname: Martino
authors.affiliation: King's College London British Heart Foundation Centre of Excellence. The Rayne Institute, St Thomas' Hospital Campus, London, SE1 7EH, UK.
authors.forename: Sharwari
authors.initials: S
authors.lastname: Verma
authors.affiliation: King's College London British Heart Foundation Centre of Excellence. The Rayne Institute, St Thomas' Hospital Campus, London, SE1 7EH, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Sicard
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Guy's Campus, King's College London, London, SE1 1UL, UK.
authors.forename: Renée
authors.initials: R
authors.lastname: Tata
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Guy's Campus, King's College London, London, SE1 1UL, UK.
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Atkinson
authors.affiliation: 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.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.affiliation: Randall Division of Cell and Molecular Biophysics, Guy's Campus, King's College London, London, SE1 1UL, UK.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Conte
authors.affiliation: King's College London British Heart Foundation Centre of Excellence. The Rayne Institute, St Thomas' Hospital Campus, London, SE1 7EH, UK.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marber
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D006801:Humans; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000201:enzymology; D019906:Nuclear Magnetic Resonance, Biomolecular; D010766:Phosphorylation; D051381:Rats; D017386:Sequence Homology, Amino Acid
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C531463:Tab1 protein, mouse; D000255:Adenosine Triphosphate; D048308:Mitogen-Activated Protein Kinase 14
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