Oscillatory dynamics arising from competitive inhibition and multisite phosphorylation
Oscillatory dynamics arising from competitive inhibition and multisite phosphorylation
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竞争性抑制和多位点磷酸化产生的振荡动力学
DOI：
10.1016/j.jtbi.2006.05.013
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发表时间：
2007-01-07
影响因子：
2
通讯作者：
Sauro, Herbert M.
中科院分区：
文献类型：
--
作者：
Chickarmane, Vijay;Kholodenko, Boris N.;Sauro, Herbert M.
对真核信号通路中蛋白质水平（p53 和 NFkB）振荡的观察越来越多。这使得人们对这种振荡可能发生的机制重新产生了兴趣。最近的计算工作表明，在 MAPK 级联中发现的多位点磷酸化机制理论上可以表现出双稳态。双稳态行为被证明是由催化多位点磷酸化循环的酶的隔离和饱和机制引起的。这些效应产生双稳态所需的正反馈。在本文中，我们描述了网络中可能发生的两种振荡动力学，两者都使用这种双稳态多位点磷酸化循环。在第一个例子中，磷酸化循环的完全磷酸化形式抑制激酶的产生，激酶对循环的非磷酸化状态进行磷酸化。该系统的动力学导致张弛振荡器。在第二个例子中，我们考虑两个循环的级联，其中激酶的完全磷酸化形式在第一个循环中磷酸化第二个循环中的未磷酸化形式。还存在反馈环路，第二个循环的完全磷酸化形式通过该反馈环路抑制第一个循环中的激酶步骤。在这种情况下，我们获得了一个环形振荡器。这两个网络都说明了多站点双稳态网络的多功能性。 (c) 2006 Elsevier Ltd. 保留所有权利。
There have been a growing number of observations of oscillating protein levels (p53 and NFkB) in eukaryotic signalling pathways. This has resulted in a renewed interest in the mechanism by which such oscillations might occur. Recent computational work has shown that a multisite phosphorylation mechanism such as that found in the MAPK cascade can theoretically exhibit bistability. The bistable behavior was shown to arise from sequestration and saturation mechanisms for the enzymes that catalyse the multisite phosphorylation cycle. These effects generate the positive feedback necessary for bistability. In this paper we describe two kinds of oscillatory dynamics which can occur in a network by which.. both use such bistable multisite phosphorylated cycles. In the first example, the fully phosphorylated form of the phosphorylated cycle represses the production of the kinase, which carries out the phosphorylation of the unphosphorylated states of the cycle. The dynamics of this system leads to a relaxation oscillator. In the second example, we consider a cascade of two cycles, in which the fully phosphorylated form of the kinase, in the first cycle.. phosphorylates the unphosphorylated forms in the second cycle. A feedback loop, by which the fully phosphorylated form of the second cycle inhibits the kinase step in the first cycle is also present. In this case we obtain a ring oscillator. Both these networks illustrate the versatility of the multisite bistable network. (c) 2006 Elsevier Ltd. All rights reserved.