ArticleThe Journal of biological chemistry2014
A systems biology analysis of apoptosome formation and apoptosis execution supports allosteric procaspase-9 activation.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- The ASC-c isoform as a modulator of inflammasome activation: Insights into molecular mechanisms and therapeutic applications.The Journal of biological chemistry · 2026Article
- Activation of caspase-9 on the apoptosome as studied by methyl-TROSY NMR.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Current trends in luminescence-based assessment of apoptosis.RSC advances · 2023Review
- Lycopene Alleviates Titanium Dioxide Nanoparticle-Induced Testicular Toxicity by Inhibiting Oxidative Stress and Apoptosis in Mice.Biological trace element research · 2022Article
- Mechanisms of Survival of Cytomegalovirus-Infected Tumor Cells.Molecular biology · 2022Article
- The apoptosome molecular timer synergises with XIAP to suppress apoptosis execution and contributes to prognosticating survival in colorectal cancer.Cell death and differentiation · 2020Article
- Anticancer activity of a novel methylated analogue of L-mimosine against an in vitro model of human malignant melanoma.Investigational new drugs · 2020Article
- The FLAME-accelerated signalling tool (FaST) for facile parallelisation of flexible agent-based models of cell signalling.NPJ systems biology and applications · 2020Article
- Transit of Procaspase-9 towards its activation. New mechanistic insights from molecular dynamics simulations.Journal of molecular modeling · 2020Article
- New insights into apoptosome structure and function.Cell death and differentiation · 2018Review
- Sulforaphane-cysteine-induced apoptosis via phosphorylated ERK1/2-mediated maspin pathway in human non-small cell lung cancer cells.Cell death discovery · 2017Article
- ASC Induces Apoptosis via Activation of Caspase-9 by Enhancing Gap Junction-Mediated Intercellular Communication.PloS one · 2017Article
- Article
- Necroptosis: A new way of dying?Cancer biology & therapy · 2016Review
Corrections and comments
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Authors and funding
2 authors.
Funding
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Abstract
The protease caspase-9 is activated on the apoptosome, a multiprotein signal transduction platform that assembles in response to mitochondria-dependent apoptosis initiation. Despite extensive molecular research, the assembly of the holo-apoptosome and the process of caspase-9 activation remain incompletely understood. Here, we therefore integrated quantitative data on the molecular interactions and proteolytic processes during apoptosome formation and apoptosis execution and conducted mathematical simulations to investigate the resulting biochemical signaling, quantitatively and kinetically. Interestingly, when implementing the homodimerization of procaspase-9 as a prerequisite for activation, the calculated kinetics of apoptosis execution and the efficacy of caspase-3 activation failed to replicate experimental data. In contrast, assuming a scenario in which procaspase-9 is activated allosterically upon binding to the apoptosome backbone, the mathematical simulations quantitatively and kinetically reproduced all experimental data. These data included a XIAP threshold concentration at which apoptosis execution is suppressed in HeLa cervical cancer cells, half-times of procaspase-9 processing, as well as the molecular timer function of the apoptosome. Our study therefore provides novel mechanistic insight into apoptosome-dependent apoptosis execution and suggests that caspase-9 is activated allosterically by binding to the apoptosome backbone. Our findings challenge the currently prevailing dogma that all initiator procaspases require homodimerization for activation.
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