University of Michigan, Department of Chemical Engineering, Ann Arbor, USA.
IET Syst Biol. 2011 Jan;5(1):27. doi: 10.1049/iet-syb.2009.0069.
The authors propose a novel minimum oscillator whereby a protein with multiple phosphorylation sites directly embedded in a negative feedback loop can exhibit oscillation. They demonstrate that if the fully phosphorylated substrate inhibits the first phosphorylation step in a cooperative manner, multisite substrates can exhibit oscillatory behaviour at the presence of a kinase and phosphatase. With a fixed number of sites, the non-linearity of the negative feedback and the substrate∕enzyme ratio must be above certain threshold values to generate undamped oscillation. There is an inverse relationship between the number of phosphorylation sites and the minimum non-linearity of the negative feedback required for oscillation; that is, the ultrasensitivity and time delay rooted in multisite phosphorylation compensate for the explicit non-linearity in the negative feedback. The period and amplitude of oscillation are mainly determined by the number of phosphorylation sites and the substrate∕enzyme ratio. The authors' results suggest that a multisite protein can be exploited for the construction of a synthetic protein oscillator featuring simplicity, robustness and tunability.
作者提出了一种新的最小振荡器，其中具有多个磷酸化位点的蛋白质直接嵌入在负反馈回路中可以表现出振荡。他们证明，如果完全磷酸化的底物以协同的方式抑制第一磷酸化步骤，那么多位点底物在存在激酶和磷酸酶的情况下可以表现出振荡行为。对于固定数量的位点，负反馈的非线性和底物/酶比必须高于一定的阈值才能产生无阻尼的振荡。磷酸化位点的数量与产生振荡所需的负反馈的最小非线性之间存在反比关系；也就是说，源于多位点磷酸化的超敏性和时滞补偿了负反馈中的显式非线性。振荡的周期和幅度主要由磷酸化位点的数量和底物/酶比决定。作者的结果表明，多位点蛋白质可用于构建具有简单性、鲁棒性和可调性的合成蛋白振荡器。
