1. Structural Biology and Molecular Biophysics
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Atomic structure of the 26S proteasome lid reveals the mechanism of deubiquitinase inhibition

  1. Corey M Dambacher
  2. Evan J Worden
  3. Mark A Herzik
  4. Andreas Martin
  5. Gabriel C Lander  Is a corresponding author
  1. The Scripps Research Institute, United States
  2. University of California, Berkeley, United States
Research Article
  • Cited 62
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Cite this article as: eLife 2016;5:e13027 doi: 10.7554/eLife.13027

Abstract

The 26S proteasome is responsible for the selective, ATP-dependent degradation of polyubiquitinated cellular proteins. Removal of ubiquitin chains from targeted substrates at the proteasome is a prerequisite for substrate processing and is accomplished by Rpn11, a deubiquitinase within the 'lid' sub-complex. Prior to the lid's incorporation into the proteasome, Rpn11 deubiquitinase activity is inhibited to prevent unwarranted deubiquitination of polyubiquitinated proteins. Here we present the atomic model of the isolated lid sub-complex, as determined by cryo-electron microscopy at 3.5 Å resolution, revealing how Rpn11 is inhibited through its interaction with a neighboring lid subunit, Rpn5. Through mutagenesis of specific residues, we describe the network of interactions that are required to stabilize this inhibited state. These results provide significant insight into the intricate mechanisms of proteasome assembly, outlining the substantial conformational rearrangements that occur during incorporation of the lid into the 26S holoenzyme, which ultimately activates the deubiquitinase for substrate degradation.

Article and author information

Author details

  1. Corey M Dambacher

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Evan J Worden

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mark A Herzik

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Andreas Martin

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Gabriel C Lander

    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, United States
    For correspondence
    glander@scripps.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Sjors HW Scheres, Medical Research Council, United Kingdom

Publication history

  1. Received: November 13, 2015
  2. Accepted: January 7, 2016
  3. Accepted Manuscript published: January 8, 2016 (version 1)
  4. Version of Record published: January 28, 2016 (version 2)

Copyright

© 2016, Dambacher 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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