1. Structural Biology and Molecular Biophysics
  2. Computational and Systems Biology

Transient protein-protein interactions perturb E. coli metabolome and cause gene dosage toxicity

  1. Sanchari Bhattacharyya
  2. Shimon Bershtein
  3. Jin Yan
  4. Tijda Argun
  5. Amy I Gilson
  6. Sunia A Trauger
  7. Eugene I Shakhnovich  Is a corresponding author
  1. Harvard University, United States
  2. Ben-Gurion University of the Negev, Israel
https://doi.org/10.7554/eLife.20309
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  1. Sanchari Bhattacharyya
  2. Shimon Bershtein
  3. Jin Yan
  4. Tijda Argun
  5. Amy I Gilson
  6. Sunia A Trauger
  7. Eugene I Shakhnovich
(2016)
Transient protein-protein interactions perturb E. coli metabolome and cause gene dosage toxicity
eLife 5:e20309.
https://doi.org/10.7554/eLife.20309
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Abstract

Gene dosage toxicity (GDT) is an important factor that determines optimal levels of protein abundances, yet its molecular underpinnings remain unknown. Here, we demonstrate that overexpression of DHFR in E. coli causes a toxic metabolic imbalance triggered by interactions with several functionally related enzymes. Though deleterious in the overexpression regime, surprisingly, these interactions are beneficial at physiological concentrations, implying their functional significance in vivo. Moreover, we found that overexpression of orthologous DHFR proteins had minimal effect on all levels of cellular organization - molecular, systems, and phenotypic, in sharp contrast to E. coli DHFR. Dramatic difference of GDT between 'E. coli's self' and 'foreign' proteins suggests the crucial role of evolutionary selection in shaping protein-protein interaction (PPI) networks at the whole proteome level. This study shows how protein overexpression perturbs a dynamic metabolon of weak yet potentially functional PPI, with consequences for the metabolic state of cells and their fitness.

Article and author information

Author details

  1. Sanchari Bhattacharyya

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3421-4755

  2. Shimon Bershtein

    Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
    Competing interests
    The authors declare that no competing interests exist.

  3. Jin Yan

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Tijda Argun

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Amy I Gilson

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2046-3603

  6. Sunia A Trauger

    Small Molecule Mass Spectrometry, Northwest Laboratories, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Eugene I Shakhnovich

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    For correspondence
    shakhnovich@chemistry.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4769-2265

Funding

National Institute of General Medical Sciences (GM111955)

  • Eugene I Shakhnovich

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

Reviewing Editor

  1. Stefan Klumpp, Max Planck Institute of Colloids and Interfaces, Germany

Version history

  1. Received: August 4, 2016
  2. Accepted: December 9, 2016
  3. Accepted Manuscript published: December 10, 2016 (version 1)
  4. Version of Record published: December 21, 2016 (version 2)

Copyright

© 2016, Bhattacharyya 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. Sanchari Bhattacharyya
  2. Shimon Bershtein
  3. Jin Yan
  4. Tijda Argun
  5. Amy I Gilson
  6. Sunia A Trauger
  7. Eugene I Shakhnovich
(2016)
Transient protein-protein interactions perturb E. coli metabolome and cause gene dosage toxicity
eLife 5:e20309.
https://doi.org/10.7554/eLife.20309

Share this article

https://doi.org/10.7554/eLife.20309

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