Nakabayashi Jun, Sasaki Akira
Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
J Theor Biol. 2006 Sep 21;242(2):280-7. doi: 10.1016/j.jtbi.2006.02.022. Epub 2006 May 2.
Apoptosis, a highly conserved form of cell suicide, is regulated by apoptotic signals and their transduction with caspases, a family of cystein proteases. Caspases are constantly expressed in the normal cells as inactive pro-enzymes. The activity of caspase is regulated by the proteolysis. Sequential proteolytic reactions of caspases are needed to execute apoptosis. Mitochondrial pathway is one of these apoptotic signal pathways, in which caspases are oligomerized into characteristic heptamer structure, called apoptosome, with caspase-9 that activate the effector caspases for apoptosis. To investigate the dynamics of signal transduction pathway regulated by oligomerization, we construct a mathematical model for Apaf-1 heptamer assembly process. The model first reveals that intermediate products can remain unconverted even after all assemble reactions are completed. The second result of the model is that the conversion efficiency of Apaf-1 heptamer assembly is maximized when the initial concentration of cytochrome c is equal to that of Apaf-1. When the concentration of cytochrome c is sufficiently larger or smaller than that of Apaf-1, the final Apaf-1 heptamer production is decreased, because intermediate Apaf-1 oligomers (tetramers and bigger oligomers), which themselves are unable to form active heptamer, accumulate too fast in the cells, choking a smooth production of Apaf-1 heptamer. Slow activation of Apaf-1 monomers and small oligomers increase the conversion efficiency. We also study the optimal number of subunits comprising an active oligomer that maximize the conversion efficiency in assembly process, and found that the tetramer is the optimum.
细胞凋亡是一种高度保守的细胞自杀形式，受凋亡信号及其通过半胱天冬酶（一类半胱氨酸蛋白酶）的转导调节。半胱天冬酶在正常细胞中以无活性的酶原形式持续表达。半胱天冬酶的活性受蛋白水解作用调节。执行细胞凋亡需要半胱天冬酶的顺序蛋白水解反应。线粒体途径是这些凋亡信号途径之一，在该途径中，半胱天冬酶与半胱天冬酶 -9 寡聚形成特征性的七聚体结构，称为凋亡小体，半胱天冬酶 -9 激活效应半胱天冬酶以引发细胞凋亡。为了研究由寡聚化调节的信号转导途径的动力学，我们构建了一个关于凋亡蛋白酶激活因子 -1（Apaf -1）七聚体组装过程的数学模型。该模型首先揭示，即使所有组装反应完成后，中间产物仍可能未被转化。该模型的第二个结果是，当细胞色素 c 的初始浓度等于 Apaf -1 的初始浓度时，Apaf -1 七聚体组装的转化效率最高。当细胞色素 c 的浓度远高于或远低于 Apaf -1 的浓度时，最终 Apaf -1 七聚体的产量会降低，因为中间的 Apaf -1 寡聚体（四聚体和更大的寡聚体）本身无法形成活性七聚体，它们在细胞中积累过快，阻碍了 Apaf -1 七聚体的顺利产生。Apaf -1 单体和小寡聚体的缓慢激活提高了转化效率。我们还研究了在组装过程中使转化效率最大化的活性寡聚体的最佳亚基数量，发现四聚体是最佳选择。
