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Heterogeneous responses to low level death receptor activation are explained by random molecular assembly of the Caspase-8 activation platform.
- Source :
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PLoS Computational Biology . 9/25/2019, Vol. 15 Issue 9, p1-22. 22p. 3 Diagrams, 4 Graphs. - Publication Year :
- 2019
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Abstract
- Ligand binding to death receptors activates apoptosis in cancer cells. Stimulation of death receptors results in the formation of intracellular multiprotein platforms that either activate the apoptotic initiator Caspase-8 to trigger cell death, or signal through kinases to initiate inflammatory and cell survival signalling. Two of these platforms, the Death-Inducing Signalling Complex (DISC) and the RIPoptosome, also initiate necroptosis by building filamentous scaffolds that lead to the activation of mixed lineage kinase domain-like pseudokinase. To explain cell decision making downstream of death receptor activation, we developed a semi-stochastic model of DISC/RIPoptosome formation. The model is a hybrid of a direct Gillespie stochastic simulation algorithm for slow assembly of the RIPoptosome and a deterministic model of downstream caspase activation. The model explains how alterations in the level of death receptor-ligand complexes, their clustering properties and intrinsic molecular fluctuations in RIPoptosome assembly drive heterogeneous dynamics of Caspase-8 activation. The model highlights how kinetic proofreading leads to heterogeneous cell responses and results in fractional cell killing at low levels of receptor stimulation. It reveals that the noise in Caspase-8 activation—exclusively caused by the stochastic molecular assembly of the DISC/RIPoptosome platform—has a key function in extrinsic apoptotic stimuli recognition. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 1553734X
- Volume :
- 15
- Issue :
- 9
- Database :
- Academic Search Index
- Journal :
- PLoS Computational Biology
- Publication Type :
- Academic Journal
- Accession number :
- 138802235
- Full Text :
- https://doi.org/10.1371/journal.pcbi.1007374