Kierzek Andrzej M, Zhou Lu, Wanner Barry L
Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK GU2 7XH.
Mol Biosyst. 2010 Mar;6(3):531-42. doi: 10.1039/b906951h. Epub 2009 Dec 2.
Two-component systems (TCSs) are prevalent signal transduction systems in bacteria that control innumerable adaptive responses to environmental cues and host-pathogen interactions. We constructed a detailed stochastic kinetic model of two component signalling based on published data. Our model has been validated with flow cytometry data and used to examine reporter gene expression in response to extracellular signal strength. The model shows that, depending on the actual kinetic parameters, TCSs exhibit all-or-none, graded or mixed mode responses. In accordance with other studies, positively autoregulated TCSs exhibit all-or-none responses. Unexpectedly, our model revealed that TCSs lacking a positive feedback loop exhibit not only graded but also mixed mode responses, in which variation of the signal strength alters the level of gene expression in induced cells while the regulated gene continues to be expressed at the basal level in a substantial fraction of cells. The graded response of the TCS changes to mixed mode response by an increase of the translation initiation rate of the histidine kinase. Thus, a TCS is an evolvable design pattern capable of implementing deterministic regulation and stochastic switches associated with both graded and threshold responses. This has implications for understanding the emergence of population diversity in pathogenic bacteria and the design of genetic circuits in synthetic biology applications. The model is available in systems biology markup language (SBML) and systems biology graphical notation (SBGN) formats and can be used as a component of large-scale biochemical reaction network models.
双组分系统（TCSs）是细菌中普遍存在的信号转导系统，可控制对环境线索和宿主-病原体相互作用的无数适应性反应。我们基于已发表的数据构建了一个详细的双组分信号传导随机动力学模型。我们的模型已通过流式细胞术数据验证，并用于研究报告基因对细胞外信号强度的表达响应。该模型表明，根据实际动力学参数，TCSs表现出全或无、分级或混合模式响应。与其他研究一致，正向自调节的TCSs表现出全或无响应。出乎意料的是，我们的模型显示，缺乏正反馈回路的TCSs不仅表现出分级响应，还表现出混合模式响应，其中信号强度的变化会改变诱导细胞中的基因表达水平，而在相当一部分细胞中，受调控的基因继续在基础水平上表达。通过增加组氨酸激酶的翻译起始速率，TCS的分级响应转变为混合模式响应。因此，TCS是一种可进化的设计模式，能够实现与分级响应和阈值响应相关的确定性调节和随机开关。这对于理解病原菌群体多样性的出现以及合成生物学应用中遗传回路的设计具有重要意义。该模型以系统生物学标记语言（SBML）和系统生物学图形符号（SBGN）格式提供，可作为大规模生化反应网络模型的一个组件使用。
