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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains
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Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains

机译：Keap1是一个叉状茎二聚体结构，具有两个大球体，包围着中间的，双甘氨酸重复序列和C端结构域

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摘要

Keap1 is a substrate adaptor of a Cullin 3-based E3 ubiquitin ligase complex that recognizes Nrf2, and also acts as a cellular sensor for xenobiotics and oxidative stresses. Nrf2 is a transcriptional factor regulating the expression of cytoprotective enzyme genes in response to such stresses. Under unstressed conditions Keap1 binds Nrf2 and results in rapid degradation of Nrf2 through the protea-some pathway. In contrast, upon exposure to oxidative and elec-trophilic stress, reactive cysteine residues in intervening region (IVR) and Broad complex, Tramtrack, and Bric-a-Brac domains of Keap1 are modified by electrophiles. This modification prevents Nrf2 from rapid degradation and induces Nrf2 activity by repression of Keap1. Here we report the structure of mouse Keap1 homo-dimer by single particle electron microscopy. Three-dimensional reconstruction at 24-A resolution revealed two large spheres attached by short linker arms to the sides of a small forked-stem structure, resembling a cherry-bob. Each sphere has a tunnel corresponding to the central hole of the β-propeller domain, as determined by x-ray crystallography. The IVR domain appears to surround the core of the β-propeller domain. The unexpected proximity of IVR to the β-propeller domain suggests that any distortions generated during modification of reactive cysteine residues in the IVR domain may send a derepression signal to the β-propeller domain and thereby stabilize Nrf2. This study thus provides a structural basis for the two-site binding and hinge-latch model of stress sensing by the Nrf2-Keap1 system.
机译：Keap1是基于Cullin 3的E3泛素连接酶复合物的底物衔接子，该复合物可识别Nrf2，也可作为异种生物和氧化应激的细胞传感器。 Nrf2是一种转录因子，可调节细胞保护酶基因的表达，以应对此类压力。在不受压力的条件下，Keap1结合Nrf2，并导致Nrf2通过蛋白酶体途径快速降解。相反，暴露于氧化和亲电子应力后，亲电试剂修饰居间区（IVR）和Keap1的Broad Complex，Tramtrack和Bric-a-Brac域的反应性半胱氨酸残基。此修饰可防止Nrf2快速降解，并通过抑制Keap1诱导Nrf2活性。在这里，我们通过单粒子电子显微镜报告小鼠Keap1同型二聚体的结构。在24-A分辨率下进行的三维重建显示出两个大球体，它们由短连接臂连接到一个小的叉状茎结构的侧面，类似于一个樱桃鲍勃。每个球体都有一个隧道，该隧道与x射线晶体学确定的β螺旋桨域的中心孔相对应。 IVR域似乎围绕着β-螺旋桨域的核心。 IVR与β螺旋桨域的意外接近表明，在IVR域中反应性半胱氨酸残基的修饰过程中产生的任何扭曲都可能向β螺旋桨域发送抑制信号，从而稳定Nrf2。因此，这项研究为Nrf2-Keap1系统进行应力感应的两点结合和铰链-闩锁模型提供了结构基础。

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    Toshihiko Ogura; Kit I. Tong; Kazuhiro Mio; Yuusuke Maruyama; Hirofumi Kurokawa; Chikara Sato; Masayuki Yamamoto;

  • 作者单位

    Neuroscience Research Institute and Biological Information Research Center, National Institute of Advanced Industrial Science and Technology (AIST),1-1-4 Umezono, Tsukuba 305-8568, Japan;

    rnDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho,Aoba-ku, Sendai 980-8575, Japan;

    rnNeuroscience Research Institute and Biological Information Research Center, National Institute of Advanced Industrial Science and Technology (AIST),1-1-4 Umezono, Tsukuba 305-8568, Japan;

    rnNeuroscience Research Institute and Biological Information Research Center, National Institute of Advanced Industrial Science and Technology (AIST),1-1-4 Umezono, Tsukuba 305-8568, Japan;

    rnDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho,Aoba-ku, Sendai 980-8575, Japan;

    rnNeuroscience Research Institute and Biological Information Research Center, National Institute of Advanced Industrial Science and Technology (AIST),1-1-4 Umezono, Tsukuba 305-8568, Japan;

    rnDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho,Aoba-ku, Sendai 980-8575, Japan;

  • 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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