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

Author

Listed:
  • Yuanchen Dong

    (Peking University
    Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Shuwen Zhang

    (Peking University
    Peking University)

  • Zhaolong Wu

    (Peking University)

  • Xuemei Li

    (School of Physics, Peking University)

  • Wei Li Wang

    (Peking University
    Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Yanan Zhu

    (Peking University
    Peking University)

  • Svetla Stoilova-McPhie

    (Harvard University)

  • Ying Lu

    (Harvard Medical School)

  • Daniel Finley

    (Harvard Medical School)

  • Youdong Mao

    (Peking University
    Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Harvard Medical School)

Abstract

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 Å 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.

Suggested Citation

  • Yuanchen Dong & Shuwen Zhang & Zhaolong Wu & Xuemei Li & Wei Li Wang & Yanan Zhu & Svetla Stoilova-McPhie & Ying Lu & Daniel Finley & Youdong Mao, 2019. "Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome," Nature, Nature, vol. 565(7737), pages 49-55, January.
  • Handle: RePEc:nat:nature:v:565:y:2019:i:7737:d:10.1038_s41586-018-0736-4
    DOI: 10.1038/s41586-018-0736-4
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    Cited by:

    1. Ian Cooney & Heidi L. Schubert & Karina Cedeno & Olivia N. Fisher & Richard Carson & John C. Price & Christopher P. Hill & Peter S. Shen, 2024. "Visualization of the Cdc48 AAA+ ATPase protein unfolding pathway," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Xiaojie Yan & Xinxin Yuan & Jianke Lv & Bing Zhang & Yongle Huang & Qianqian Li & Jinfeng Ma & Yanran Li & Xiaolu Wang & Yao Li & Ying Yu & Quanyan Liu & Tong Liu & Wenyi Mi & Cheng Dong, 2024. "Molecular basis of SAP05-mediated ubiquitin-independent proteasomal degradation of transcription factors," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Ka Ying Sharon Hung & Sven Klumpe & Markus R. Eisele & Suzanne Elsasser & Geng Tian & Shuangwu Sun & Jamie A. Moroco & Tat Cheung Cheng & Tapan Joshi & Timo Seibel & Duco Dalen & Xin-Hua Feng & Ying L, 2022. "Allosteric control of Ubp6 and the proteasome via a bidirectional switch," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    4. Maximilian Fottner & Maria Weyh & Stefan Gaussmann & Dominic Schwarz & Michael Sattler & Kathrin Lang, 2021. "A modular toolbox to generate complex polymeric ubiquitin architectures using orthogonal sortase enzymes," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    5. Yang Xu & Han Han & Ian Cooney & Yuxuan Guo & Noah G. Moran & Nathan R. Zuniga & John C. Price & Christopher P. Hill & Peter S. Shen, 2022. "Active conformation of the p97-p47 unfoldase complex," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    6. Indrajit Sahu & Sachitanand M. Mali & Prasad Sulkshane & Cong Xu & Andrey Rozenberg & Roni Morag & Manisha Priyadarsini Sahoo & Sumeet K. Singh & Zhanyu Ding & Yifan Wang & Sharleen Day & Yao Cong & O, 2021. "The 20S as a stand-alone proteasome in cells can degrade the ubiquitin tag," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    7. Nathan Jespersen & Kai Ehrenbolger & Rahel R. Winiger & Dennis Svedberg & Charles R. Vossbrinck & Jonas Barandun, 2022. "Structure of the reduced microsporidian proteasome bound by PI31-like peptides in dormant spores," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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