Sun Jianqiang, Yi Ming, Yang Lijian, Wei Wenbin, Ding Yiming, Jia Ya
Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing, China.
Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China; National Center for Mathematics and Interdisciplinary Sciences, Chinese Academy of Sciences, Beijing, China.
Biophys J. 2014 Mar 4;106(5):1215-26. doi: 10.1016/j.bpj.2014.01.036.
The processive phosphorylation mechanism becomes important when there is macromolecular crowding in the cytoplasm. Integrating the processive phosphorylation mechanism with the traditional distributive one, we propose a mixed dual-site phosphorylation (MDP) mechanism in a single-layer phosphorylation cycle. Further, we build a degree model by applying the MDP mechanism to a three-layer mitogen-activated protein kinase (MAPK) cascade. By bifurcation analysis, our study suggests that the crowded-environment-induced pseudoprocessive mechanism can qualitatively change the response of this biological network. By adjusting the degree of processivity in our model, we find that the MAPK cascade is able to switch between the ultrasensitivity, bistability, and oscillatory dynamical states. Sensitivity analysis shows that the theoretical results remain unchanged within a reasonably chosen variation of parameter perturbation. By scaling the reaction rates and also introducing new connections into the kinetic scheme, we further construct a proportion model of the MAPK cascade to validate our findings. Finally, it is illustrated that the spatial propagation of the activated MAPK signal can be improved (or attenuated) by increasing the degree of processivity of kinase (or phosphatase). Our research implies that the MDP mechanism makes the MAPK cascade become a flexible signal module, and the coexistence of processive and distributive phosphorylation mechanisms enhances the tunability of the MAPK cascade.
当细胞质中存在大分子拥挤现象时，持续性磷酸化机制变得至关重要。将持续性磷酸化机制与传统的分布式磷酸化机制相结合，我们在单层磷酸化循环中提出了一种混合双位点磷酸化（MDP）机制。此外，我们通过将MDP机制应用于三层丝裂原活化蛋白激酶（MAPK）级联反应构建了一个程度模型。通过分岔分析，我们的研究表明，拥挤环境诱导的假持续性机制可以定性地改变这个生物网络的响应。通过在我们的模型中调整持续性程度，我们发现MAPK级联反应能够在超敏感性、双稳态和振荡动力学状态之间切换。敏感性分析表明，在合理选择的参数扰动变化范围内，理论结果保持不变。通过缩放反应速率并在动力学方案中引入新的连接，我们进一步构建了MAPK级联反应的比例模型以验证我们的发现。最后，结果表明，通过增加激酶（或磷酸酶）的持续性程度，可以改善（或减弱）活化的MAPK信号的空间传播。我们的研究表明，MDP机制使MAPK级联反应成为一个灵活的信号模块，持续性和分布式磷酸化机制的共存增强了MAPK级联反应的可调性。
