Molecular Titration and Ultrasensitivity in Regulatory Networks
Molecular Titration and Ultrasensitivity in Regulatory Networks
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DOI：
10.1016/j.jmb.2008.09.079
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发表时间：
2008-12-31
影响因子：
5.6
通讯作者：
Louis, Matthieu
中科院分区：
文献类型：
--
作者：
Buchler, Nicolas E.;Louis, Matthieu
当一个活性蛋白质被一个阻遏物隔离到一个非活性复合物上时，就会发生蛋白质隔离。使用数学和计算建模，我们展示了这种调节机制（称为“分子滴定”）如何产生超灵敏或“全或无”的反应，相当于高度合作的过程。输入-输出反应的超灵敏性主要由两个参数决定：二聚体解离常数和阻遏物浓度。由于体内浓度可通过多种机制调节，因此分子滴定代表了产生超灵敏度的灵活机制。使用生理参数，我们报告如何在体内蛋白质降解的细节影响的强度的超灵敏度在稳态。考虑到发育系统经常将信号转换为与稳态不相容的时间尺度上的细胞命运决定，我们进一步研究了分子滴定是否可以在生理相关的时间间隔内产生超灵敏的反应。使用果蝇体细胞性别决定作为一个发展的范例，我们证明，分子滴定可以产生超灵敏度的时间尺度上兼容大多数细胞命运的决定。基因复制后的功能丧失突变可以产生显性负性，其滴定并与原始蛋白质竞争。显性负性在基因调控回路中非常丰富，我们的研究结果表明，分子滴定可能会在这些网络中产生超灵敏的反应。(C)2008爱思唯尔有限公司保留所有权利。
Protein sequestration occurs when an active protein is sequestered by a repressor unto an inactive complex. Using mathematical and computational modeling, we show how this regulatory mechanism (called "molecular titration") can generate ultrasensitive or "all-or-none" responses that are equivalent to highly cooperative processes. The ultrasensitive nature of the input-output response is mainly determined by two parameters: the dimer dissociation constant and the repressor concentration. Because in vivo concentrations are tunable through a variety of mechanisms, molecular titration represents a flexible mechanism for generating ultrasensitivity. Using physiological parameters, we report how details of in vivo protein degradation affect the strength of the ultrasensitivity at steady state. Given that developmental systems often transduce signals into cell-fate decisions on timescales incompatible with steady state, we further examine whether molecular titration can produce ultrasensitive responses within physiologically relevant time intervals. Using Drosophila somatic sex determination as a developmental paradigm, we demonstrate that molecular titration can generate ultrasensitivity on timescales compatible with most cell-fate decisions. Gene duplication followed by loss-of-function mutations can create dominant negatives that titrate and compete with the original protein. Dominant negatives are abundant in gene regulatory circuits, and our results suggest that molecular titration might be generating an ultrasensitive response in these networks. (C) 2008 Elsevier Ltd. All rights reserved.