Reversible Phosphorylation Subserves Robust Circadian Rhythms by Creating a Switch in Inactivating the Positive Element
Reversible Phosphorylation Subserves Robust Circadian Rhythms by Creating a Switch in Inactivating the Positive Element
复制标题
可逆磷酸化通过创建一个使积极元素失活的开关来维持稳健的昼夜节律
DOI：
10.1016/j.bpj.2009.09.008
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发表时间：
2009-12-02
影响因子：
3.4
通讯作者：
Wang, Wei
中科院分区：
文献类型：
--
作者：
Cheng, Zhang;Liu, Feng;Wang, Wei
蛋白质的可逆磷酸化在昼夜节律系统中普遍存在，但它在产生节律性中所起的作用尚未完全了解。大多数昼夜节律的共同机制涉及正负元素之间的负反馈回路。在这里，我们建立了一个最小的模型粗糙脉孢菌的昼夜节律钟的基础上的核心负反馈回路和蛋白质频率（FRQ）依赖的磷酸化的白色衣领复合物（WCC）。该模型可以再现时钟的基本特征，如周期长度，相位关系，以及对亮/暗周期的夹带。我们发现，由于零阶超灵敏度，WCC的活性可以由FRQ以开关式的方式控制。当FRQ水平从下方越过阈值时，WCC将被禁用。因此，转录激活中的低协同性对于昼夜节律是足够的，并且活性WCC的水平表现出尖峰振荡。这种振荡对分子噪声是鲁棒的，并且可以有助于控制昼夜输出。因此，核心负反馈与正元素的磷酸化一起可以确保稳健的昼夜节律。我们的工作为生物钟中翻译后修饰的关键作用提供了见解。
Reversible phosphorylation of proteins is ubiquitous in circadian systems, but the role it plays in generating rhythmicity is not completely understood. A common mechanism for most circadian rhythms involves a negative feedback loop between the positive and negative elements. Here, we built a minimal model for the Neurospora crassa circadian clock based on the core negative feedback loop and the protein FREQUENCY (FRQ)-dependent phosphorylation of the White Collar Complex (WCC). The model can reproduce basic features of the clock, such as the period length, phase relationship, and entrainment to light/dark cycles. We found that the activity of WCC can be controlled by FRQ in a switchlike manner owing to zero-order ultrasensitivity. WCC is inactivated when FRQ level crosses a threshold from below. As a result, low cooperativity in transcriptional activation is sufficient for circadian rhythms, and the level of active WCC exhibits spiky oscillations. Such oscillations are robust to molecular noise and may subserve controlling circadian output. Therefore, the core negative feedback together with phosphorylation of the positive element can ensure robust circadian rhythms. Our work provides insights into the critical roles of posttranslational modification in circadian clocks.