Ryu Seongho, Lin Shih-Chieh, Ugel Nadia, Antoniotti Marco, Mishra Bud
Department of Biology, New York University, New York, NY, USA.
Syst Synth Biol. 2008 Jun;2(1-2):49-66. doi: 10.1007/s11693-009-9022-y. Epub 2009 Mar 31.
Caspase-9 is the protease that mediates the intrinsic pathway of apoptosis, a type of cell death. Activation of caspase-9 is a multi-step process that requires dATP or ATP and involves at least two proteins, cytochrome c and Apaf-1. In this study, we mathematically model caspase-9 activation by using a system of ordinary differential equations (an ODE model) generated by a systems biology tool Simpathica-a simulation and reasoning system, developed to study biological pathways. A rudimentary version of "model checking" based on comparing simulation data with that obtained from a recombinant system of caspase-9 activation, provided several new insights into regulation of this protease. The model predicts that the activation begins with binding of dATP to Apaf-1, which initiates the interaction between Apaf-1 and cytochrome c, thus forming a complex that oligomerizes into an active caspase-9 holoenzyme via a linear binding model with cooperative interaction rather than through network formation.
半胱天冬酶 -9是介导细胞凋亡（一种细胞死亡类型）内在途径的蛋白酶。半胱天冬酶 -9的激活是一个多步骤过程，需要dATP或ATP，并且至少涉及两种蛋白质，即细胞色素c和凋亡蛋白酶激活因子 -1（Apaf-1）。在本研究中，我们通过使用由系统生物学工具Simpathica（一个为研究生物途径而开发的模拟和推理系统）生成的常微分方程组（一个ODE模型），对半胱天冬酶 -9的激活进行数学建模。基于将模拟数据与从半胱天冬酶 -9激活的重组系统获得的数据进行比较的一个初步版本的“模型检查”，为该蛋白酶的调控提供了几个新的见解。该模型预测，激活始于dATP与Apaf-1的结合，这启动了Apaf-1与细胞色素c之间的相互作用，从而形成一个复合物，该复合物通过具有协同相互作用的线性结合模型而非通过网络形成寡聚化为活性半胱天冬酶 -9全酶。
