title: Enhancement of tunability of MAPK cascade due to coexistence of processive and distributive phosphorylation mechanisms.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Sun
authors.affiliation: 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. Electronic address: yiming@wipm.ac.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Yi
authors.affiliation: Department of Physics and Institute of Biophysics, Huazhong Normal University, Wuhan, China.
authors.forename: Lijian
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Physics and Institute of Biophysics, Huazhong Normal University, Wuhan, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Wei
authors.affiliation: Key Laboratory of Magnetic Resonance in Biological Systems, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Physics and Institute of Biophysics, Huazhong Normal University, Wuhan, China. Electronic address: jiay@phy.ccnu.edu.cn.
authors.forename: Ya
authors.initials: Y
authors.lastname: Jia
mesh_terms: D004058:Diffusion; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D010766:Phosphorylation