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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding
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Oxidation-induced intramolecular disulfide bond inactivates mitogen-activated protein kinase kinase 6 by inhibiting ATP binding

机译：氧化诱导的分子内二硫键通过抑制ATP结合而使丝裂原活化的蛋白激酶激酶6失活

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摘要

Mitogen-activated protein kinase kinase 6 (MKK6) is a member of the mitogen-activated protein kinase (MAPK) kinase (MAP2K) subfamily that specifically phosphorylates and activates the p38 MAPKs. Based on both biochemical and cellular assays, we found that MKK6 was extremely sensitive to oxidation: It was inactivated by oxidation and its kinase activity was fully restored upon treatment with a reducing agent. Detailed mechanistic studies showed that cysteines 109 and 196, two of the six cysteines in MKK6, formed an intramolecular disulfide bond upon oxidation that inactivated MKK6 by inhibiting its ATP binding. This mechanism is distinct from that seen in other redox-sensitive kinases. The two cysteines involved in intramolecular disulfide formation are conserved in all seven members of the MAP2K family. Consistently, we confirmed that other MAP2Ks were also sensitive to oxidation. Our work reveals that MKK6 and other MAP2KS are a distinct class of cellular redox sensors.
机译：丝裂原激活的蛋白激酶激酶6（MKK6）是有丝分裂原激活的蛋白激酶（MAPK）激酶（MAP2K）亚家族的成员，可特异性磷酸化和激活p38 MAPK。根据生化和细胞分析，我们发现MKK6对氧化极为敏感：它被氧化灭活，并且在用还原剂处理后其激酶活性得以完全恢复。详细的机理研究表明，半胱氨酸109和196，即MKK6中的六个半胱氨酸中的两个，在氧化时形成了分子内二硫键，该二硫键通过抑制MKK6的ATP结合而使其失活。该机制不同于其他氧化还原敏感激酶中的机制。参与分子内二硫键形成的两个半胱氨酸在MAP2K家族的所有七个成员中都是保守的。一致地，我们确认其他MAP2K对氧化也敏感。我们的工作表明，MKK6和其他MAP2KS是一类独特的细胞氧化还原传感器。

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    Yarui Diao; Wei Liu; Catherine C. L Wong; Xi Wang; Kaman Lee; Po-yan Cheung; Lifeng Pan; Tao Xu; Jiahuai Han; John R. Yates III; Mingjie Zhang; Zhenguo Wu;

  • 作者单位

    Department of Biochemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China;

    Department of Biochemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China;

    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Biochemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China;

    Department of Biochemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China;

    Department of Biochemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China;

    Department of Biochemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China;

    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;

    School of Life Sciences, Xiamen University, Xiamen 361005,China;

    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037;

    Department of Biochemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China;

    Department of Biochemistry, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Hong Kong, China;

  • 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);
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