Nonlinear protein degradation and the function of genetic circuits
Nonlinear protein degradation and the function of genetic circuits
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DOI：
10.1073/pnas.0409553102
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发表时间：
2005-07-05
影响因子：
11.1
通讯作者：
Hwa, T
中科院分区：
文献类型：
--
作者：
Buchler, NE;Gerland, U;Hwa, T
大多数遗传电路的功能要求电路组件具有足够程度的协同性。虽然协作机制已经在转录起始控制的背景下进行了最广泛的研究，但参与电路操作的其他过程的协作也可以发挥重要作用。在这项工作中，我们研究了一个简单的动力学来源的多聚体蛋白质的非线性降解的协同性。大量的实验证据表明，蛋白质亚基在多聚体复合物中结合时降解速度较慢，我们称之为“协同稳定性”。对于二聚体转录因子，这种效应导致降解速率的浓度依赖性，因为在低浓度下占主导地位的单体将更快地降解。因此，协同稳定性可以有效地拓宽体内蛋白质水平的可及范围。通过对细菌中两个示例性遗传电路的理论分析，我们表明，这种增加的范围对于遗传电路的鲁棒操作以及它们的可进化性是重要的。我们的计算表明，单体和二聚体的降解速率之间的几倍差异已经可以大大提高这些电路的功能。我们讨论了合作稳定性的分子机制及其在自然或工程系统中的发生。我们的研究结果表明，合作的稳定性需要明确考虑和定量的特点，在任何系统的实验或理论研究的基因电路。
The functions of most genetic circuits require a sufficient degree of cooperativity in the circuit components. Although mechanisms of cooperativity have been studied most extensively in the context of transcriptional initiation control, cooperativity from other processes involved in the operation of the circuits can also play important roles. In this work, we examine a simple kinetic source of cooperativity stemming from the nonlinear degradation of multimeric proteins. Ample experimental evidence suggests that protein subunits can degrade less rapidly when associated in multimeric complexes, an effect we refer to as "cooperative stability." For dimeric transcription factors, this effect leads to a concentration-dependence in the degradation rate because monomers, which are predominant at low concentrations, will be more rapidly degraded. Thus, cooperative stability can effectively widen the accessible range of protein levels in vivo. Through theoretical analysis of two exemplary genetic circuits in bacteria, we show that such an increased range is important for the robust operation of genetic circuits as well as their evolvability. Our calculations demonstrate that a few-fold difference between the degradation rate of monomers and dimers can already enhance the function of these circuits substantially. We discuss molecular mechanisms of cooperative stability and their occurrence in natural or engineered systems. Our results suggest that cooperative stability needs to be considered explicitly and characterized quantitatively in any systematic experimental or theoretical study of gene circuits.