Vera Julio, Millat Thomas, Kolch Walter, Wolkenhauer Olaf
University of Rostock, Rostock, Germany.
BMC Syst Biol. 2008 Oct 31;2:92. doi: 10.1186/1752-0509-2-92.
Signalling pathways are complex systems in which not only simple monomeric molecules interact, but also more complex structures that include constitutive or induced protein assemblies. In particular, the hetero-and homo-dimerisation of proteins is a commonly encountered motif in signalling pathways. Several authors have suggested in recent times that dimerisation relates to a series of physical and biological outcomes used by the cell in the regulation of signal transduction.
In this paper we investigate the role of homodimerisation in receptor-protein transducer interactions. Towards this end, mathematical modelling is used to analyse the features of such kind of interactions and to predict the behaviour of the system under different experimental conditions. A kinetic model in which the interaction between homodimers provokes a dual mechanism of activation (single and double protein transducer activation at the same time) is proposed. In addition, we analyse under which conditions the use of a power-law representation for the system is useful. Furthermore, we investigate the dynamical consequences of this dual mechanism and compare the performance of the system in different simulated experimental conditions.
The analysis of our mathematical model suggests that in receptor-protein interacting systems with dual mechanism there may be a shift between double and single activation in a way that intense double protein transducer activation could initiate and dominate the signal in the short term (getting a fast intense signal), while single protein activation could control the system in the medium and long term (when input signal is weaker and decreases slowly). Our investigation suggests that homodimerisation and oligomerisation are mechanisms used to enhance and regulate the dynamic properties of the initial steps in signalling pathways.
信号通路是复杂的系统，其中不仅有简单的单体分子相互作用，还包括组成型或诱导型蛋白质组装体等更复杂的结构。特别是，蛋白质的异源和同源二聚化是信号通路中常见的基序。近年来，几位作者提出二聚化与细胞在信号转导调节中使用的一系列物理和生物学结果有关。
在本文中，我们研究了同源二聚化在受体 - 蛋白质转导子相互作用中的作用。为此，使用数学建模来分析这类相互作用的特征，并预测不同实验条件下系统的行为。提出了一个动力学模型，其中同源二聚体之间的相互作用引发了双重激活机制（同时激活单个和双个蛋白质转导子）。此外，我们分析了在哪些条件下对系统使用幂律表示是有用的。此外，我们研究了这种双重机制的动力学后果，并比较了系统在不同模拟实验条件下的性能。
我们数学模型的分析表明，在具有双重机制的受体 - 蛋白质相互作用系统中，双激活和单激活之间可能会发生转变，即强烈的双蛋白质转导子激活可能在短期内启动并主导信号（获得快速强烈的信号），而单蛋白质激活可能在中长期控制该系统（当输入信号较弱且缓慢下降时）。我们的研究表明，同源二聚化和寡聚化是用于增强和调节信号通路初始步骤动态特性的机制。
