TY - JOUR
T1 - Transient protein-protein interactions perturb E. coli metabolome and cause gene dosage toxicity
AU - Bhattacharyya, Sanchari
AU - Bershtein, Shimon
AU - Yan, Jin
AU - Argun, Tijda
AU - Gilson, Amy I.
AU - Trauger, Sunia A.
AU - Shakhnovich, Eugene I.
N1 - Funding Information: We thank Bharat Adkar for valuable discussions and help with analysis of the proteomics and metabolomics data, Adrian Serohijos and Michael Manhart for valuable discussions and suggestions. This work was funded by NIH RO1 GM111955. 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. Publisher Copyright: © Bhattacharyya et al.
PY - 2016/12/10
Y1 - 2016/12/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85006920592&partnerID=8YFLogxK
U2 - 10.7554/eLife.20309
DO - 10.7554/eLife.20309
M3 - Article
SN - 2050-084X
VL - 5
JO - eLife
JF - eLife
IS - DECEMBER2016
M1 - e20309
ER -