Predicting regulation of the phosphorylation cycle of KaiC clock protein using mathematical analysis
Predicting regulation of the phosphorylation cycle of KaiC clock protein using mathematical analysis
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DOI：
10.1177/0748730406291329
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Mochizuki, Atsushi
中科院分区：
文献类型：
--
作者：
Takigawa-Imamura, Hisako;Mochizuki, Atsushi
蓝藻时钟蛋白 KaiC 通过转录、翻译和磷酸化的节律来调节昼夜节律。即使在无转录条件下，KaiC 磷酸化也会在昼夜节律周期中持续存在，并通过孵育 KaiC、KaiA 和 KaiB 在体外重建。这为由于时钟蛋白之间的相互作用而发生的昼夜节律振荡提供了一个新的视角。作者利用数学模型研究了无转录 KaiC 磷酸化循环的机制。他们根据 Kitayama 等人通过实验提出的可能的 KaiC 行为开发了一个简单的模型。 （2003，EMBO J，22：2127-2134）。他们假设 KaiC-KaiA 复合物的形成，随后游离 KaiA 分子的减少，可能会减弱 KaiC 磷酸化速率，并在系统中充当负反馈。然而，该模型不足以产生 KaiC 磷酸化循环。作者开发了该模型的通用版本，并确定了生成 KaiC 磷酸化循环的必要条件。线性稳定性分析表明，当受体反应与效应器之间的反馈距离足够远时，就会发生振荡。此外，他们将封闭系统中的负反馈调节分为两种类型：不稳定抑制和稳定抑制。基于这一结果，作者预测，除了已确定的 KaiC 状态之外，KaiC 磷酸化和复合物形成之间还必须存在另一个未知状态。通过将未知状态纳入之前的模型中，他们实现了计算机模拟中让人想起 KaiC 磷酸化循环的周期性模式。该结果意味着KaiC-KaiA复合物的形成需要超过I步的翻译后修饰，包括KaiC的磷酸化或构象变化。
The cyanobacterial clock protein KaiC regulates the circadian cycle by exhibiting rhythms in transcription, translation, and phosphorylation. KaiC phosphorylation persists in circadian cycling even under transcription-less conditions and was reconstituted in vitro by incubating KaiC, KaiA, and KaiB. This presents a novel perspective for circadian oscillation occurring due to interactions between clock proteins. Using mathematical models, the authors investigated the mechanism for the transcription-less KaiC phosphorylation cycle. They developed a simple model based on the possible KaiC behavior, which is experimentally suggested by Kitayama et al. (2003, EMBO J, 22:2127-2134). They hypothesized that the KaiC-KaiA complex formation, followed by a decrease in free KaiA molecules, may attenuate the KaiC phosphorylation rate, and it acts as negative feedback in the system. However, this model was shown not to be adequate to generate the KaiC phosphorylation cycle. The authors developed the general version of the model and determined the necessary condition to generate the KaiC phosphorylation cycle. Linear stability analysis revealed that oscillations can occur when the distance of feedback between the recipient reaction and the effector is far enough. Furthermore, they classified negative feedback regulations in the closed system into 2 types: destabilizing inhibition and stabilizing inhibition. Based on this result, the authors predicted that, in addition to the identified states of KaiC, another unknown state must be present between KaiC phosphorylation and the complex formation. By incorporating the unknown state into the previous model, they realized the periodic pattern reminiscent of the KaiC phosphorylation cycle in computer simulation. This result implies that the KaiC-KaiA complex formation requires more than I step of posttranslational modification, including phosphorylation or conformational change of KaiC.