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Structural insight into the autoinhibition mechanism of AMP-activated protein kinase

机译：AMP活化蛋白激酶自抑制机制的结构洞察

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摘要

The AMP-activated protein kinase (AMPK) is characterized by its ability to bind to AMP, which enables it to adjust enzymatic activity by sensing the cellular energy status and maintain the balance between ATP production and consumption in eukaryotic cells. It also has important roles in the regulation of cell growth and proliferation, and in the establishment and maintenance of cell polarity. These important functions have rendered AMPK an important drug target for obesity, type 2 diabetes and cancer treatments. However, the regulatory mechanism of AMPK activity by AMP binding remains unsolved. Here we report the crystal structures of an unphosphorylated fragment of the AMPK a-subunit (KD-AID) from Schizosaccharomyces pombe that contains both the catalytic kinase domain and an autoinhibi-tory domain (AID), and of a phosphorylated kinase domain from Saccharomyces cerevisiae (Snfl-pKD). The AID binds, from the 'backside', to the hinge region of its kinase domain, forming contacts with both ammo-terminal and carboxy-terminal lobes. Structural analyses indicate that AID binding might constrain the mobility of helix aC, hence resulting in an autoinhibited KD-AID with much lower kinase activity than that of the kinase domain alone. AMP activates AMPK both allosterically and by inhibiting dephosphorylation. Further in vitro kinetic studies demonstrate that disruption of the KD-AID interface reverses the autoinhibition and these AMPK heterotrimeric mutants no longer respond to the change in AMP concentration. The structural and biochemical data have shown the primary mechanism of AMPK autoinhibition and suggest a conformational switch model for AMPK activation by AMP.
机译：AMP激活的蛋白激酶（AMPK）具有与AMP结合的能力，使其能够通过感知细胞能量状态来调节酶活性，并维持真核细胞中ATP产生与消耗之间的平衡。它还在调节细胞生长和增殖以及建立和维持细胞极性中具有重要作用。这些重要功能使AMPK成为肥胖，2型糖尿病和癌症治疗的重要药物靶标。但是，AMP结合的AMPK活性调节机制仍未解决。在这里我们报告来自裂殖酵母的AMPK a亚基（KD-AID）的未磷酸化片段的晶体结构，其中既包含催化激酶结构域又具有自抑制域（AID），也来自酿酒酵母的磷酸化激酶结构域。 （Snfl-pKD）。 AID从“背面”结合到其激酶结构域的铰链区，形成与氨基末端和羧基末端叶的接触。结构分析表明，AID结合可能会限制螺旋aC的迁移，从而导致自抑制的KD-AID的激酶活性比单独的激酶域低得多。 AMP通过变构和抑制去磷酸化激活AMPK。进一步的体外动力学研究表明，KD-AID接口的破坏会逆转自抑制作用，并且这些AMPK异源三聚体突变体不再响应AMP浓度的变化。结构和生化数据显示了AMPK自动抑制的主要机制，并提出了AMP激活AMPK的构象转换模型。

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  • 来源
    《Nature》 |2009年第25期|1146-1149|共4页
  • 作者

    Lei Chen; Zhi-Hao Jiao; Li-Sha Zheng; Yuan-Yuan Zhang; Shu-Tao Xie; Zhi-Xin Wang; Jia-Wei Wu;

  • 作者单位

    MOE Key Laboratory of Bioinformatics, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China These authors contributed equally to this work;

    MOE Key Laboratory of Bioinformatics, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China These authors contributed equally to this work;

    Institute of Biophysics and Graduate University, Chinese Academy of Sciences, Beijing 100101, China These authors contributed equally to this work;

    MOE Key Laboratory of Bioinformatics, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China;

    MOE Key Laboratory of Bioinformatics, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China;

    MOE Key Laboratory of Bioinformatics, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China Institute of Biophysics and Graduate University, Chinese Academy of Sciences, Beijing 100101, China;

    MOE Key Laboratory of Bioinformatics, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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