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

Elife. 2016 Dec 10;5:e20309. doi: 10.7554/eLife.20309.


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.

Keywords: E. coli; biophysics; computational biology; gene dosage toxicity; protein crowding in cytoplasm; protein-protein interactions; structural biology; systems biology.

MeSH terms

  • Escherichia coli / genetics
  • Escherichia coli / metabolism*
  • Escherichia coli Proteins / metabolism
  • Escherichia coli Proteins / toxicity*
  • Gene Dosage*
  • Metabolome
  • Protein Binding
  • Protein Interaction Maps
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / toxicity*
  • Tetrahydrofolate Dehydrogenase / metabolism
  • Tetrahydrofolate Dehydrogenase / toxicity*


  • Escherichia coli Proteins
  • Recombinant Proteins
  • Tetrahydrofolate Dehydrogenase