Center for Advanced Biotechnology and Medicine, Department of Biochemistry and Molecular Biology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Center for Advanced Biotechnology and Medicine, Department of Biochemistry and Molecular Biology, Rutgers University-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Cell Rep. 2018 Sep 11;24(11):3061-3071.e6. doi: 10.1016/j.celrep.2018.08.023.
A fundamental trade-off between rapid response and optimal expression of genes below cytotoxic levels exists for many signaling circuits, particularly for positively autoregulated systems with an inherent response delay. Here, we describe a regulatory scheme in the E. coli PhoB-PhoR two-component system, which overcomes the cost of positive feedback and achieves both fast and optimal steady-state response for maximal fitness across different environments. Quantitation of the cellular activities enables accurate modeling of the response dynamics to describe how requirements for optimal protein concentrations place limits on response speed. An observed fast response that exceeds the limit led to the prediction and discovery of a coupled negative autoregulation, which allows fast gene expression without increasing steady-state levels. We demonstrate the fitness advantages for the coupled feedbacks in both dynamic and stable environments. Such regulatory schemes offer great flexibility for accurate control of gene expression levels and dynamics upon environmental changes.
许多信号转导回路存在快速响应和细胞毒性水平以下的基因最佳表达之间的基本权衡，特别是对于具有固有响应延迟的正自调控系统。在这里，我们描述了大肠杆菌 PhoB-PhoR 双组分系统中的一种调控方案，该方案克服了正反馈的代价，并在不同环境下实现了最大适应性的快速和最佳稳态响应。细胞活性的定量使响应动力学的精确建模成为可能，从而描述了最佳蛋白质浓度的要求如何限制响应速度。观察到的超过限制的快速响应导致了耦合负反馈的预测和发现，该反馈允许快速基因表达而不增加稳态水平。我们在动态和稳定环境中证明了耦合反馈的适应性优势。这种调控方案为环境变化时基因表达水平和动力学的精确控制提供了极大的灵活性。
