National Laboratory of Solid State Microstructures and Department of Physics, Nanjing University, Nanjing, China.
Biophys J. 2009 Dec 2;97(11):2867-75. doi: 10.1016/j.bpj.2009.09.008.
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.
蛋白质的可逆磷酸化在生物钟系统中普遍存在，但它在产生节律性方面的作用尚未完全了解。大多数生物钟的一个常见机制涉及正、负元件之间的负反馈回路。在这里，我们基于核心负反馈回路和 FRQ（FREQUENCY）依赖性的白色领结复合物（WCC）磷酸化，构建了一个粗糙脉孢菌生物钟的最小模型。该模型可以再现生物钟的基本特征，如周期长度、相位关系以及对光/暗周期的适应。我们发现，由于零阶超敏性，FRQ 可以以开关方式控制 WCC 的活性。当 FRQ 水平从下方越过阈值时，WCC 失活。因此，转录激活的低协同性足以产生生物钟节律，并且活性 WCC 的水平表现出尖峰振荡。这种振荡对分子噪声具有鲁棒性，可能用于控制生物钟输出。因此，核心负反馈加上正元件的磷酸化可以确保稳健的生物钟节律。我们的工作为翻译后修饰在生物钟中的关键作用提供了新的见解。
