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

Sanchari Bhattacharyya, Shimon Bershtein, Jin Yan, Tijda Argun, Amy I. Gilson, Sunia A. Trauger, Eugene I. Shakhnovich

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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.

Original languageEnglish
Article numbere20309
Issue numberDECEMBER2016
StatePublished - 10 Dec 2016

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology
  • General Neuroscience


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