title: Transient protein-protein interactions perturbE. colimetabolome and cause gene dosage toxicity.
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 inE. colicauses 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 significancein 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 toE. coliDHFR. 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.
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States.
authors.forename: Sanchari
authors.identifier: 0000-0003-3421-4755
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
authors.forename: Shimon
authors.initials: S
authors.lastname: Bershtein
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States.|College of Chemical Engineering, Sichuan University, Chengdu, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States.
authors.forename: Tijda
authors.initials: T
authors.lastname: Argun
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States.
authors.forename: Amy I
authors.identifier: 0000-0003-2046-3603
authors.initials: AI
authors.lastname: Gilson
authors.affiliation: Small Molecule Mass Spectrometry, Northwest Laboratories, Harvard University, Cambridge, United States.
authors.forename: Sunia A
authors.initials: SA
authors.lastname: Trauger
authors.affiliation: Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States.
authors.forename: Eugene I
authors.identifier: 0000-0002-4769-2265
authors.initials: EI
authors.lastname: Shakhnovich
mesh_terms: D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000378:metabolism / Q000633:toxicity*; D018628:Gene Dosage; D055442:Metabolome; D011485:Protein Binding; D060066:Protein Interaction Maps; D011994:Recombinant Proteins / Q000378:metabolism / Q000633:toxicity*; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism / Q000633:toxicity*
chemical_list: D029968:Escherichia coli Proteins; D011994:Recombinant Proteins; D013762:Tetrahydrofolate Dehydrogenase
keywords: E. coli; biophysics; computational biology; gene dosage toxicity; protein crowding in cytoplasm; protein-protein interactions; structural biology; systems biology