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    A temperature-dependent conformational shift in p38α MAPK substrate–binding region associated with changes in substrate phosphorylation profile

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    Author
    Deredge, D.
    Wintrode, P.L.
    Tulapurkar, M.E.
    Nagarsekar, A.
    Zhang, Y.
    Weber, D.J.
    Shapiro, P.
    Hasday, J.D.
    Date
    2019
    Journal
    Journal of Biological Chemistry
    Publisher
    American Society for Biochemistry and Molecular Biology Inc.
    Type
    Article
    
    Metadata
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    See at
    https://doi.org/10.1074/jbc.RA119.007525
    Abstract
    Febrile-range hyperthermia worsens and hypothermia mitigates lung injury, and temperature dependence of lung injury is blunted by inhibitors of p38 mitogen-activated protein kinase (MAPK). Of the two predominant p38 isoforms, p38α is proinflammatory and p38β is cytoprotective. Here, we analyzed the temperature dependence of p38 MAPK activation, substrate interaction, and tertiary structure. Incubating HeLa cells at 39.5 °C stimulated modest p38 activation, but did not alter tumor necrosis factor-α (TNFα)-induced p38 activation. In in vitro kinase assays containing activated p38α and MAPK-activated kinase-2 (MK2), MK2 phosphorylation was 14.5-fold greater at 39.5 °C than at 33 °C. By comparison, we observed only 3.1- and 1.9-fold differences for activating transcription factor-2 (ATF2) and signal transducer and activator of transcription- 1α (STAT1α) and a 7.7-fold difference for p38β phosphorylation of MK2. The temperature dependence of p38α:substrate binding affinity, as measured by surface plasmon resonance, paralleled substrate phosphorylation. Hydrogen- deuterium exchangeMS(HDX-MS) of p38α performed at 33, 37, and 39.5 °C indicated temperature-dependent conformational changes in an α helix near the common docking and glutamate: aspartate substrate-binding domains at the known binding site for MK2. In contrast, HDX-MS analysis of p38β did not detect significant temperature-dependent conformational changes in this region. We observed no conformational changes in the catalytic domain of either isoform and no corresponding temperature dependence in the C-terminal p38α-interacting region of MK2. Because MK2 participates in the pathogenesis of lung injury, the observed changes in the structure and function of proinflammatory p38α may contribute to the temperature dependence of acute lung injury.
    Sponsors
    This work was supported by National Institutes of Health Grant R01HL69057 and Veterans Affairs Grant BX002143.
    Keyword
    Acute Lung Injury--physiopathology
    Body Temperature Changes
    p38 Mitogen-Activated Protein Kinases
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85071467396&doi=10.1074%2fjbc.RA119.007525&partnerID=40&md5=eb0412129b2ad6b57d4922169a9f4354; http://hdl.handle.net/10713/10839
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.RA119.007525
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