KaiABC蓝藻生物钟中蛋白质相互作用和磷仿动力学的计算模拟
Computational modeling of protein interactions and phosphoform kinetics in the KaiABC cyanobacterial circadian clock
摘要：
来自蓝藻的KaiABC生物钟是唯一已知的三蛋白质振荡系统，它可以在细胞外重建，并在各种分子状态变量中显示持续的周期性动力学。尽管最近有许多实验和理论研究，但关于负责在蛋白质的分子组装/分解以及KaiC单体的位点依赖性磷酸化和去磷酸化方面产生这种~24小时时钟的中心机制存在几个开放性问题。模拟蛋白质-蛋白质相互作用和磷酸化反应的分析拟合部分反应的实验数据的约束下支持的中央振荡机制KaiB诱导KaiA螯合KaiABC复合物与Ser 431磷酸化KaiC六聚体的程度。一个简单的双态确定性模型在Ser 431和Thr 432位点的磷酸化程度方面可以再现先前观察到的昼夜节律振荡的四个人口单体磷酸化的波形，振幅和相位。这表明循环磷酸化方案（涉及相邻Ser 431和Thr 432位点之间的协同性）对于产生振荡是不必要的。时钟的直接模拟预测与KaiA螯合和释放相关的仅丝氨酸单体亚基的最小数量，突出单体交换在快速同步中的作用，并预测每个KaiC六聚体螯合的KaiA二聚体的平均数量。
英文摘要：
The KaiABC circadian clock from cyanobacteria is the only known three-protein oscillatory system which can be reconstituted outside the cell and which displays sustained periodic dynamics in various molecular state variables. Despite many recent experimental and theoretical studies there are several open questions regarding the central mechanism(s) responsible for creating this ~24 hour clock in terms of molecular assembly/disassembly of the proteins and site-dependent phosphorylation and dephosphorylation of KaiC monomers. Simulations of protein-protein interactions and phosphorylation reactions constrained by analytical fits to partial reaction experimental data support the central mechanism of oscillation as KaiB-induced KaiA sequestration in KaiABC complexes associated with the extent of Ser431 phosphorylation in KaiC hexamers. A simple two-state deterministic model in terms of the degree of phosphorylation of Ser431 and Thr432 sites alone can reproduce the previously observed circadian oscillation in the four population monomer phosphoforms in terms of waveform, amplitude and phase. This suggests that a cyclic phosphorylation scheme (involving cooperativity between adjacent Ser431 and Thr432 sites) is not necessary for creating oscillations. Direct simulations of the clock predict the minimum number of serine-only monomer subunits associated with KaiA sequestration and release, highlight the role of monomer exchange in rapid synchronization, and predict the average number of KaiA dimers sequestered per KaiC hexamer.
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