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.
Original language | English (US) |
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Pages (from-to) | 49-66 |
Number of pages | 18 |
Journal | Systems and Synthetic Biology |
Volume | 2 |
Issue number | 1-2 |
DOIs | |
State | Published - Jun 2008 |
Keywords
- Apoptosis
- Apoptosome
- Caspase-9 ODE model
- Computational systems biology
- Model checking
- Model comparison and selection
ASJC Scopus subject areas
- Biotechnology
- Bioengineering
- Molecular Biology