An opposite role for tau in circadian rhythms revealed by mathematical modeling
An opposite role for tau in circadian rhythms revealed by mathematical modeling
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DOI：
10.1073/pnas.0604511103
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发表时间：
2006-07-11
影响因子：
11.1
通讯作者：
Forger, Daniel B.
中科院分区：
文献类型：
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作者：
Gallego, Monica;Eide, Erik J.;Forger, Daniel B.
生物钟的周期约为24小时（昼夜节律），存在于大多数生物体和时间的各种功能，包括睡眠-觉醒周期，激素释放，生物发光和核心体温波动。我们对生物钟机制的大部分理解来自于对影响昼夜节律行为的特定突变的识别。酪蛋白激酶I（CKI）中的一种广泛研究的突变，CKI tau（tau）突变体，已经显示在体外引起激酶功能的丧失，但是很难将这种功能的丧失与目前的生物钟功能模型相协调。在这里，我们表明，数学建模预测相反，激酶突变体CKI β（tau）增加激酶活性，我们验证了这一预测实验。CKI β（tau）是一种高度特异性的功能获得性突变，其增加昼夜节律调节剂PER 1和PER 2的体内磷酸化和降解。这些发现通过实验验证了复杂生物功能的数学建模方法，阐明了CKI在时钟中的作用，并证明了特定突变可以是功能的获得和丧失，这取决于底物。
Biological clocks with a period of approximate to 24 h (circadian) exist in most organisms and time a variety of functions, including sleep-wake cycles, hormone release, bioluminescence, and core body temperature fluctuations. Much of our understanding of the clock mechanism comes from the identification of specific mutations that affect circadian behavior. A widely studied mutation in casein kinase I (CKI), the CKI epsilon(tau) mutant, has been shown to cause a loss of kinase function in vitro, but it has been difficult to reconcile this loss of function with the current model of circadian clock function. Here we show that mathematical modeling predicts the opposite, that the kinase mutant CKI epsilon(tau) increases kinase activity, and we verify this prediction experimentally. CKI epsilon(tau) is a highly specific gain-of-function mutation that increases the in vivo phosphorylation and degradation of the circadian regulators PER1 and PER2. These findings experimentally validate a mathematical modeling approach to a complex biological function, clarify the role of CKI in the clock, and demonstrate that a specific mutation can be both a gain and a loss of function depending on the substrate.