Theory and Bio-Systems, Max Planck Institute of Colloids and Interfaces, Potsdam, Germany.
PLoS Comput Biol. 2019 Aug 1;15(8):e1006979. doi: 10.1371/journal.pcbi.1006979. eCollection 2019 Aug.
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 system's tRNA and codon compositions. We find that protein synthesis reacts ultrasensitively to a decrease in the elongation factor's 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.
蛋白质合成的调控和维持对所有生物体都是至关重要的，因此在细胞水平上是攻击和防御的关键目标。在这里，我们从数学上分析了蛋白质合成对延伸因子 EF-Tu 和/或核糖体抑制的敏感性，这取决于系统的 tRNA 和密码子组成。我们发现，对于密码子使用和 tRNA 浓度之间失衡的系统，蛋白质合成对延伸因子浓度的降低反应非常敏感。对于平衡良好的 tRNA/密码子组成，核糖体的抑制比 EF-Tu 的抑制更有效地阻碍蛋白质合成。我们的预测得到了重新评估的实验数据以及独立计算机模拟的支持。描述的超敏性不仅使 EF-Tu 成为蛋白质合成抑制抗生素的独特靶标。它还可以通过毒素-抗毒素系统介导持久细胞的形成。tRNA/密码子组成的强烈影响为人类线粒体 EF-Tu 突变引起的疾病的组织特异性以及 EF-Tu 靶向药物用于组织特异性治疗提供了基础。
