Efficiency of protein synthesis inhibition depends on tRNA and codon compositions

Abstract

Regulation and maintenance of protein synthesis are vital to all organisms and are thus key targets of attack and defense at the cellular level. Here, we mathematically analyze protein synthesis for its sensitivity to the inhibition of elongation factor EF-Tu and/or ribosomes in dependence of the systems tRNA and codon compositions. We find that protein synthesis reacts ultrasensitively to a decrease in the elongation factors concentration for systems with an imbalance between codon usages and tRNA concentrations. For well-balanced tRNA/codon compositions, protein synthesis is impeded more effectively by the inhibition of ribosomes instead of EF-Tu. Our predictions are supported by re-evaluated experimental data as well as by independent computer simulations. Not only does the described ultrasensitivity render EF-Tu a distinguished target of protein synthesis inhibiting antibiotics. It may also enable persister cell formation mediated by toxin-antitoxin systems. The strong impact of the tRNA/codon composition provides a basis for tissue-specificities of disorders caused by mutations of human mitochondrial EF-Tu as well as for the potential use of EF-Tu targeting drugs for tissue-specific treatments.\n\nAuthor SummaryWe predict and analyze the response of differently composed protein synthesis systems to the inhibition of elongation factor EF-Tu and/or ribosomes. The study reveals a strong interdependency of a protein synthesis systems composition and its susceptibility to inhibition. This interdependency defines a generic mechanism that provides a common basis for a variety of seemingly unrelated phenomena including, for example, persister cell formation and tissue-specificity of certain mitochondrial diseases. The described mechanism applies to simple artificial translation systems as well as to complex protein synthesis in vivo.