1. Physics of Living Systems
  2. Structural Biology and Molecular Biophysics

An empirical energy landscape reveals mechanism of proteasome in polypeptide translocation

  1. Rui Fang
  2. Jason Hon
  3. Mengying Zhou
  4. Ying Lu  Is a corresponding author
  1. Harvard Medical School, United States
https://doi.org/10.7554/eLife.71911
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  1. Rui Fang
  2. Jason Hon
  3. Mengying Zhou
  4. Ying Lu
(2022)
An empirical energy landscape reveals mechanism of proteasome in polypeptide translocation
eLife 11:e71911.
https://doi.org/10.7554/eLife.71911
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Abstract

The ring-like ATPase complexes in the AAA+ family perform diverse cellular functions that require coordination between the conformational transitions of their individual ATPase subunits1,2. How the energy from ATP hydrolysis is captured to perform mechanical work by these coordinated movements is unknown. In this study, we developed a novel approach for delineating the nucleotide-dependent free-energy landscape (FEL) of the proteasome's heterohexameric ATPase complex based on complementary structural and kinetic measurements. We used the FEL to simulate the dynamics of the proteasome and quantitatively evaluated the predicted structural and kinetic properties. The FEL model predictions are consistent with a wide range of experimental observations in this and previous studies and suggested novel mechanistic features of the proteasomal ATPases. We find that the cooperative movements of the ATPase subunits result from the design of the ATPase hexamer entailing a unique free-energy minimum for each nucleotide-binding status. ATP hydrolysis dictates the direction of substrate translocation by triggering an energy-dissipating conformational transition of the ATPase complex.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 3,4,5. The original images for the single-molecule experiments are available on Dryad (https://doi.org/10.5061/dryad.t1g1jwt2t). The source code is available in GitHub (https://github.com/luyinghms/Proteasome-FEL-model.git)

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Rui Fang

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Jason Hon

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Mengying Zhou

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Ying Lu

    Department of Systems Biology, Harvard Medical School, Boston, United States
    For correspondence
    ying_lu@hms.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3516-7735

Funding

National Institute of General Medical Sciences (GM134064-01)

  • Ying Lu

Edward Mallinckrodt, Jr. Foundation

  • Ying Lu

Harvard Medical School (Dean's initiative award)

  • Ying Lu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. James M Berger, Johns Hopkins University School of Medicine, United States

Version history

  1. Preprint posted: June 22, 2021 (view preprint)
  2. Received: July 3, 2021
  3. Accepted: January 17, 2022
  4. Accepted Manuscript published: January 20, 2022 (version 1)
  5. Version of Record published: February 17, 2022 (version 2)

Copyright

© 2022, Fang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Rui Fang
  2. Jason Hon
  3. Mengying Zhou
  4. Ying Lu
(2022)
An empirical energy landscape reveals mechanism of proteasome in polypeptide translocation
eLife 11:e71911.
https://doi.org/10.7554/eLife.71911

Share this article

https://doi.org/10.7554/eLife.71911

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