Ortega Fernando, Garcés José L, Mas Francesc, Kholodenko Boris N, Cascante Marta
Centre for Research in Theoretical Chemistry, Scientific Park of Barcelona, Spain.
FEBS J. 2006 Sep;273(17):3915-26. doi: 10.1111/j.1742-4658.2006.05394.x.
Previous studies have suggested that positive feedback loops and ultrasensitivity are prerequisites for bistability in covalent modification cascades. However, it was recently shown that bistability and hysteresis can also arise solely from multisite phosphorylation. Here we analytically demonstrate that double phosphorylation of a protein (or other covalent modification) generates bistability only if: (a) the two phosphorylation (or the two dephosphorylation) reactions are catalyzed by the same enzyme; (b) the kinetics operate at least partly in the zero-order region; and (c) the ratio of the catalytic constants of the phosphorylation and dephosphorylation steps in the first modification cycle is less than this ratio in the second cycle. We also show that multisite phosphorylation enlarges the region of kinetic parameter values in which bistability appears, but does not generate multistability. In addition, we conclude that a cascade of phosphorylation/dephosphorylation cycles generates multiple steady states in the absence of feedback or feedforward loops. Our results show that bistable behavior in covalent modification cascades relies not only on the structure and regulatory pattern of feedback/feedforward loops, but also on the kinetic characteristics of their component proteins.
先前的研究表明，正反馈回路和超敏感性是共价修饰级联反应中双稳性的先决条件。然而，最近有研究表明，双稳性和滞后现象也可能仅由多位点磷酸化产生。在此，我们通过分析证明，蛋白质的双重磷酸化（或其他共价修饰）仅在以下条件下才会产生双稳性：（a）两个磷酸化（或两个去磷酸化）反应由同一种酶催化；（b）动力学至少部分在零级区域起作用；（c）第一个修饰循环中磷酸化和去磷酸化步骤的催化常数之比小于第二个循环中的该比例。我们还表明，多位点磷酸化扩大了出现双稳性的动力学参数值范围，但不会产生多稳态。此外，我们得出结论，在没有反馈或前馈回路的情况下，磷酸化/去磷酸化循环级联会产生多个稳态。我们的结果表明，共价修饰级联反应中的双稳行为不仅依赖于反馈/前馈回路的结构和调节模式，还依赖于其组成蛋白质的动力学特征。
