Mathematical modeling of the formation of apoptosome in intrinsic pathway of apoptosis

Seongho Ryu, Shih Chieh Lin, Nadia Ugel, Marco Antoniotti, Bud Mishra

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)49-66
Number of pages18
JournalSystems and Synthetic Biology
Volume2
Issue number1-2
DOIs
StatePublished - 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

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