1. Computational and Systems Biology
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Quantitative time-resolved analysis reveals intricate, differential regulation of standard- and immuno-proteasomes

  1. Juliane Liepe
  2. Hermann-Georg Holzhütter
  3. Elena Bellavista
  4. Peter M Kloetzel
  5. Michael PH Stumpf  Is a corresponding author
  6. Michele Mishto
  1. Imperial College London, United Kingdom
  2. Charité - Universitätsmedizin Berlin, Germany
  3. University of Bologna, Italy
  4. Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, United Kingdom
Research Article
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Cite this article as: eLife 2015;4:e07545 doi: 10.7554/eLife.07545

Abstract

Proteasomal protein degradation is a key determinant of protein half-life and hence of cellular processes ranging from basic metabolism to a host of immunological processes. Despite its importance the mechanisms regulating proteasome activity are only incompletely understood. Here we use an iterative and tightly integrated experimental and modelling approach to develop, explore and validate mechanistic models of proteasomal peptide-hydrolysis dynamics. The 20S proteasome is a dynamic enzyme and its activity varies over time because of interactions between substrates and products and the proteolytic and regulatory sites; the locations of these sites and the interactions between them are predicted by the model, and experimentally supported. The analysis suggests that the rate-limiting step of hydrolysis is the transport of the substrates into the proteasome. The transport efficiency varies between human standard- and immuno-proteasomes thereby impinging upon total degradation rate and substrate cleavage-site usage.

Article and author information

Author details

  1. Juliane Liepe

    Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Hermann-Georg Holzhütter

    Institut für Biochemie, Charité - Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Elena Bellavista

    Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum, University of Bologna, Bologna, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Peter M Kloetzel

    Institut für Biochemie, Charité - Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael PH Stumpf

    Imperial College London, Centre for Integrative Systems Biology and Bioinformatics, Department of Life Sciences, London, United Kingdom
    For correspondence
    m.stumpf@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  6. Michele Mishto

    Institut für Biochemie, Charité - Universitätsmedizin Berlin, Berlin, Germany
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. John Kuriyan, Howard Hughes Medical Institute, University of California, Berkeley, United States

Publication history

  1. Received: March 17, 2015
  2. Accepted: September 18, 2015
  3. Accepted Manuscript published: September 22, 2015 (version 1)
  4. Version of Record published: October 20, 2015 (version 2)

Copyright

© 2015, Liepe 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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