Kinetic approaches to lactose operon induction and bimodality
Kinetic approaches to lactose operon induction and bimodality
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DOI：
10.1016/j.jtbi.2013.02.005
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发表时间：
2013-05-21
影响因子：
2
通讯作者：
Michel, Denis
中科院分区：
文献类型：
--
作者：
Michel, Denis
当分子相互作用与电路动力学相比足够快时，准平衡近似是可以接受的，但当细胞活动受罕见事件支配时，准平衡近似不再被允许。一个典型的例子是乳糖操纵子（lac），它是最著名的转录调控范例之一，至今仍有多种理论共存来描述它的行为。紫胶系统一般用平衡常数来分析，这与Novick和Weiner（1957）长期提出的单事件假设相矛盾。酶诱导是一种全有或全无的现象。Proc. Natl. Acad. Sci. USA 43，553-566）和最近在（Choi等人，2008.随机单分子事件触发细菌细胞的表型转换。Science 322，442-446）。在本报告中，一个乳糖阻遏物（LacI）介导的DNA免疫沉淀实验表明，在体内建立的天然Lad-lac DNA复合物是非常紧密和长寿的乳糖表达动力学的时间尺度相比，这可能在功能上断开流产的表达爆发，并禁止使用标准模式的乳糖双稳态。作为替代方案，纯粹的动力学机制，检查其能力，以限制诱导，通过：（i）广泛分散的去阻遏有关的主要是向后不对称随机游走的到达时间方差和（ii）诱导阈值产生在一个单一的窗口去阻遏没有诉诸非线性多聚体结合和希尔功能。考虑到乳糖阻遏物从乳糖启动子中完全脱离是瞬时逐步机制的概率结果，足以解释S形乳糖反应随时间和诱导剂浓度的变化。这种S形形状可以被误解为经典上用来解释双稳性的平衡协同性现象，但据报道在这个系统中很弱。(C)2013爱思唯尔有限公司保留所有权利。
The quasi-equilibrium approximation is acceptable when molecular interactions are fast enough compared to circuit dynamics, but is no longer allowed when cellular activities are governed by rare events. A typical example is the lactose operon (lac), one of the most famous paradigms of transcription regulation, for which several theories still coexist to describe its behaviors. The lac system is generally analyzed by using equilibrium constants, contradicting single-event hypotheses long suggested by Novick and Weiner (1957). Enzyme induction as an all-or-none phenomenon. Proc. Natl. Acad. Sci. USA 43, 553-566) and recently refined in the study of (Choi et al., 2008. A stochastic single-molecule event triggers phenotype switching of a bacterial cell. Science 322, 442-446). In the present report, a lac repressor (LacI)-mediated DNA immunoprecipitation experiment reveals that the natural Lad-lac DNA complex built in vivo is extremely tight and long-lived compared to the time scale of lac expression dynamics, which could functionally disconnect the abortive expression bursts and forbid using the standard modes of lac bistability. As alternatives, purely kinetic mechanisms are examined for their capacity to restrict induction through: (i) widely scattered derepression related to the arrival time variance of a predominantly backward asymmetric random walk and (ii) an induction threshold arising in a single window of derepression without recourse to nonlinear multimeric binding and Hill functions. Considering the complete disengagement of the lac repressor from the lac promoter as the probabilistic consequence of a transient stepwise mechanism, is sufficient to explain the sigmoidal lac responses as functions of time and of inducer concentration. This sigmoidal shape can be misleadingly interpreted as a phenomenon of equilibrium cooperativity classically used to explain bistability, but which has been reported to be weak in this system. (C) 2013 Elsevier Ltd. All rights reserved.