• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Molecular mechanism of APC/C activation by mitotic phosphorylation
【24h】

Molecular mechanism of APC/C activation by mitotic phosphorylation

机译：有丝分裂磷酸化激活APC / C的分子机制

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

In eukaryotes, the anaphase-promoting complex (APC/C, also known as the cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle proteins to coordinate chromosome segregation in mitosis and entry into the G1 phase(1,2). The catalytic activity of the APC/C and its ability to specify the destruction of particular proteins at different phases of the cell cycle are controlled by its interaction with two structurally related coactivator subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons(3), and enhance the affinity of the APC/C for its cognate E2 (refs 4-6). During mitosis, cyclin-dependent kinase (Cdk) and polo-like kinase (Plk) control Cdc20- and Cdh1-mediated activation of the APC/C. Hyperphosphorylation of APC/C subunits, notably Apc1 and Apc3, is required for Cdc20 to activate the APC/C7-12, whereas phosphorylation of Cdh1 prevents its association with the APC/C-9,C-13,C-14. Since both coactivators associate with the APC/C through their common C-box(15) and Ile-Arg tail motifs(16,17), the mechanism underlying this differential regulation is unclear, as is the role of specific APC/C phosphorylation sites. Here, using cryo-electron microscopy and biochemical analysis, we define the molecular basis of how phosphorylation of human APC/C allows for its control by Cdc20. An auto-inhibitory segment of Apc1 acts as a molecular switch that in apo unphosphorylated APC/C interacts with the C-box binding site and obstructs engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it from the C-box-binding site. Efficient phosphorylation of the auto-inhibitory segment, and thus relief of auto-inhibition, requires the recruitment of Cdk-cyclin in complex with a Cdk regulatory subunit (Cks) to a hyperphosphorylated loop of Apc3. We also find that the small-molecule inhibitor, tosyl-l-arginine methyl ester, preferentially suppresses APC/C-Cdc20 rather than APC/CCdh1, and interacts with the binding sites of both the C-box and Ile-Arg tail motifs. Our results reveal the mechanism for the regulation of mitotic APC/C by phosphorylation and provide a rationale for the development of selective inhibitors of this state.
机译：在真核生物中，后期促进复合物（APC / C，也称为环体）调节特定细胞周期蛋白的泛素依赖性蛋白水解，以协调有丝分裂中的染色体分离并进入G1期（1,2）。 APC / C的催化活性及其指定在细胞周期不同阶段破坏特定蛋白质的能力，受其与两个结构相关的共激活子亚基Cdc20和Cdh1相互作用的控制。共激活剂可识别底物降解子（3），并增强APC / C对同源E2的亲和力（参考文献4-6）。在有丝分裂期间，细胞周期蛋白依赖性激酶（Cdk）和polo样激酶（Plk）控制Cdc20和Cdh1介导的APC / C激活。 Cdc20激活APC / C7-12需要APC / C亚基（尤其是Apc1和Apc3）的超磷酸化，而Cdh1的磷酸化会阻止其与APC / C-9，C-13，C-14缔合。由于两种共激活剂均通过其共同的C-box（15）和Ile-Arg尾巴基序（16,17）与APC / C缔合，因此这种差异调节的机制尚不清楚，具体APC / C磷酸化位点的作用也是如此。在这里，我们使用低温电子显微镜和生化分析，定义了人类APC / C磷酸化如何通过Cdc20对其进行控制的分子基础。 Apc1的自抑制节段充当分子开关，在载脂蛋白未磷酸化的APC / C中与C-box结合位点相互作用并阻碍Cdc20的结合。自身抑制区段的磷酸化将其从C-box结合位点移开。有效抑制自身抑制区段的磷酸化，从而减轻自身抑制作用，需要将具有Cdk调节亚基（Cks）的Cdk-cyclin募集到Apc3的超磷酸化环上。我们还发现，小分子抑制剂，甲苯磺酰基-1-精氨酸甲酯，优先抑制APC / C-Cdc20而不是APC / CCdh1，并与C-box和Ile-Arg尾部基序的结合位点相互作用。我们的结果揭示了通过磷酸化调节有丝分裂APC / C的机制，并为开发这种状态的选择性抑制剂提供了依据。

著录项

  • 来源
    《Nature》 |2016年第7602期|260-264|共5页
  • 作者

    Zhang Suyang; Chang Leifu; Alfieri Claudio; Zhang Ziguo; Yang Jing; Maslen Sarah; Skehel Mark; Barford David;

  • 作者单位

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

    MRC Lab Mol Biol, Francis Crick Ave, Cambridge CB2 0QH, England;

  • 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);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号