Shimon Bershtein - Transient and functional protein-protein interactions perturb metabolon and cause gene dosage toxicity

Gene dosage toxicity (GDT) is an important factor that determines optimal levels of
protein abundances, yet its molecular underpinnings remain unknown. 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.
We show how protein overexpression perturbs a dynamic metabolon of weak yet
potentially functional PPI, with consequences for the metabolic state of cells
and their fitness.