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Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome

机译：底物结合的人26S蛋白酶体的低温EM结构和动力学。

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摘要

The proteasome is an ATP-dependent, 2.5-megadalton molecular machine that is responsible for selective protein degradation in eukaryotic cells. Here we present cryo-electron microscopy structures of the substrate-engaged human proteasome in seven conformational states at 2.8-3.6 angstrom resolution, captured during breakdown of a polyubiquitylated protein. These structures illuminate a spatiotemporal continuum of dynamic substrate-proteasome interactions from ubiquitin recognition to substrate translocation, during which ATP hydrolysis sequentially navigates through all six ATPases. There are three principal modes of coordinated hydrolysis, featuring hydrolytic events in two oppositely positioned ATPases, in two adjacent ATPases and in one ATPase at a time. These hydrolytic modes regulate deubiquitylation, initiation of translocation and processive unfolding of substrates, respectively. Hydrolysis of ATP powers a hinge-like motion in each ATPase that regulates its substrate interaction. Synchronization of ATP binding, ADP release and ATP hydrolysis in three adjacent ATPases drives rigid-body rotations of substrate-bound ATPases that are propagated unidirectionally in the ATPase ring and unfold the substrate.
机译：蛋白酶体是依赖ATP的2.5兆达尔顿分子机器，负责真核细胞中蛋白质的选择性降解。在这里，我们介绍了在7.8-3.6埃分辨率下以七种构象状态与底物结合的人类蛋白酶体的冷冻电子显微镜结构，该过程是在多泛素化蛋白分解过程中捕获的。这些结构阐明了从泛素识别到底物易位的动态底物-蛋白酶体相互作用的时空连续体，在此期间ATP水解依次遍历所有六个ATPase。协调水解有三种主要模式，一次在两个相对定位的ATPase，两个相邻的ATPase和一个ATPase中发生水解。这些水解模式分别调节底物的去泛素化，起始易位和进行性展开。 ATP的水解为每个ATPase中的铰链状运动提供动力，从而调节其底物相互作用。 ATP结合，ADP释放和ATP水解在三个相邻ATPase中的同步驱动底物结合的ATPase的刚体旋转，后者在ATPase环中单向传播并展开底物。

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  • 来源
    《Nature》 |2019年第7737期|49-55|共7页
  • 作者

    Dong Yuanchen; Zhang Shuwen; Wu Zhaolong; Li Xuemei; Wang Wei Li; Zhu Yanan; Stoilova-McPhie Svetla; Lu Ying; Finley Daniel; Mao Youdong;

  • 作者单位

    Peking Univ, Sch Phys, State Key Lab Artificial Microstruct & Mesoscop P, Beijing, Peoples R China|Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Boston, MA 02115 USA|Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA|Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA;

    Peking Univ, Sch Phys, State Key Lab Artificial Microstruct & Mesoscop P, Beijing, Peoples R China|Peking Univ, Ctr Quantitat Biol, Beijing, Peoples R China;

    Peking Univ, Sch Phys, State Key Lab Artificial Microstruct & Mesoscop P, Beijing, Peoples R China;

    Peking Univ, Sch Phys, Electron Microscopy Lab, Beijing, Peoples R China;

    Peking Univ, Sch Phys, State Key Lab Artificial Microstruct & Mesoscop P, Beijing, Peoples R China|Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Boston, MA 02115 USA|Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA|Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA;

    Peking Univ, Sch Phys, State Key Lab Artificial Microstruct & Mesoscop P, Beijing, Peoples R China|Peking Univ, Ctr Quantitat Biol, Beijing, Peoples R China;

    Harvard Univ, Ctr Nanoscale Syst, Cambridge, MA 02138 USA;

    Harvard Med Sch, Dept Syst Biol, Boston, MA USA;

    Harvard Med Sch, Dept Cell Biol, Boston, MA USA;

    Peking Univ, Sch Phys, State Key Lab Artificial Microstruct & Mesoscop P, Beijing, Peoples R China|Dana Farber Canc Inst, Intel Parallel Comp Ctr Struct Biol, Boston, MA 02115 USA|Dana Farber Canc Inst, Dept Canc Immunol & Virol, Boston, MA 02115 USA|Harvard Med Sch, Dept Microbiol & Immunobiol, Boston, MA 02115 USA|Peking Univ, Ctr Quantitat Biol, Beijing, Peoples R China|Peking Univ, Sch Phys, Electron Microscopy Lab, Beijing, Peoples R 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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