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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation
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Molecular basis of Tank-binding kinase 1 activation by transautophosphorylation

机译：转运结合磷酸激活Tank结合激酶1的分子基础

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摘要

Tank-binding kinase (TBK)1 plays a central role in innate immunity: it serves as an integrator of multiple signals induced by receptor-mediated pathogen detection and as a modulator of IFN levels. Efforts to better understand the biology of this key immunological factor have intensified recently as growing evidence implicates aberrant TBK1 activity in a variety of autoimmune diseases and cancers. Nevertheless, key molecular details of TBK1 regulation and substrate selection remain unanswered. Here, structures of phos-phorylated and unphosphorylated human TBK1 kinase and ubiq-uitin-like domains, combined with biochemical studies, indicate a molecular mechanism of activation via transautophosphorylation. These TBK1 structures are consistent with the tripartite architecture observed recently for the related kinase IKK|), but domain contributions toward target recognition appear to differ for the two enzymes. In particular, both TBK1 autoactivation and substrate specificity are likely driven by signal-dependent colocalization events.
机译：储罐结合激酶（TBK）1在先天免疫中起着核心作用：它是受体介导的病原体检测所诱导的多个信号的整合剂，也是IFN水平的调节剂。随着越来越多的证据表明在各种自身免疫性疾病和癌症中，TBK1活性异常，人们越来越多地努力更好地了解这一关键免疫因素的生物学特性。然而，TBK1调控和底物选择的关键分子细节仍未得到解答。在这里，磷酸化和未磷酸化的人TBK1激酶和泛素类似结构域的结构，结合生化研究，表明了通过反式自磷酸化激活的分子机制。这些TBK1结构与最近在相关激酶IKK |上观察到的三重结构一致，但是两种酶对靶标识别的域贡献似乎不同。特别地，TBK1自动激活和底物特异性都可能由信号依赖性共定位事件驱动。

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  • 作者

    Xiaolei Ma; Elizabeth Helgason; Qui T.Phung; Clifford L Quan; Rekha S.lyer; Michelle W.Lee; Krista K.Bowman; Melissa A.Starovasnik; Erin C.Dueber;

  • 作者单位

    Departments of Structural Biology, Genentech, South San Francisco, CA 94080;

    Departments of Early Discovery Biochemistry, and Genentech, South San Francisco, CA 94080;

    Departments of Protein Chemistry, Genentech, South San Francisco, CA 94080;

    Departments of Early Discovery Biochemistry, and Genentech, South San Francisco, CA 94080;

    Departments of Structural Biology, Genentech, South San Francisco, CA 94080;

    Departments of Protein Chemistry, Genentech, South San Francisco, CA 94080;

    Departments of Structural Biology, Genentech, South San Francisco, CA 94080;

    Departments of Structural Biology, Genentech, South San Francisco, CA 94080;

    Departments of Early Discovery Biochemistry, and Genentech, South San Francisco, CA 94080;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    kinase activation; crystallography;

    机译：激酶激活;晶体学;

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