title: Mathematical modeling of the formation of apoptosome in intrinsic pathway of apoptosis.
abstract: 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.
authors.affiliation: Department of Biology, New York University, New York, NY, USA.
authors.forename: Seongho
authors.initials: S
authors.lastname: Ryu
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Lin
authors.forename: Nadia
authors.initials: N
authors.lastname: Ugel
authors.forename: Marco
authors.initials: M
authors.lastname: Antoniotti
authors.forename: Bud
authors.initials: B
authors.lastname: Mishra