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kallenberger1

kallenberger1

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Reactions

reaction_1

FADD > DISC

reaction_10

p18 > p18inactive

reaction_11

Bid > tBid

reaction_12

PrNES_mCherry > PrNES + mCherry

reaction_13

PrER_mGFP > PrER + mGFP

reaction_2

DISC > FADD

reaction_3

p55free + DISC > DISCp55

reaction_4

DISCp55 > p30

reaction_5

p43 > p18 + DISC

reaction_6

DISCp55 > p43

reaction_7

DISCp55 > p43

reaction_8

p30 > p18 + DISC

reaction_9

p30 > p18 + DISC

Parameters

Global parameters

Fixed species

Initial values

Functions and Rules

Assignment rules

CD95act = pow(CD95, 3.0) * pow(KDL, 2.0) * CD95L / ((CD95L + KDL) * (pow(CD95, 2.0) * pow(KDL, 2.0) + KDR * pow(CD95L, 2.0) + 2.0 * KDR * KDL * CD95L + KDR * pow(KDL, 2.0)))

Function definitions

Events

Constraints

Note that constraints are not enforced in simulations. It remains the responsibility of the user to verify that simulation results satisfy these constraints.


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Intra- and interdimeric caspase-8 self-cleavage controls strength and timing of CD95-induced apoptosis.

  • Stefan M Kallenberger
  • Joel Beaudouin
  • Juliane Claus
  • Carmen Fischer
  • Peter K Sorger
  • Stefan Legewie
  • Roland Eils
Sci Signal 2014; 7 (316):
Abstract
Apoptosis in response to the ligand CD95L (also known as Fas ligand) is initiated by caspase-8, which is activated by dimerization and self-cleavage at death-inducing signaling complexes (DISCs). Previous work indicated that the degree of substrate cleavage by caspase-8 determines whether a cell dies or survives in response to a death stimulus. To determine how a death ligand stimulus is effectively translated into caspase-8 activity, we assessed this activity over time in single cells with compartmentalized probes that are cleaved by caspase-8 and used multiscale modeling to simultaneously describe single-cell and population data with an ensemble of single-cell models. We derived and experimentally validated a minimal model in which cleavage of caspase-8 in the enzymatic domain occurs in an interdimeric manner through interaction between DISCs, whereas prodomain cleavage sites are cleaved in an intradimeric manner within DISCs. Modeling indicated that sustained membrane-bound caspase-8 activity is followed by transient cytosolic activity, which can be interpreted as a molecular timer mechanism reflected by a limited lifetime of active caspase-8. The activation of caspase-8 by combined intra- and interdimeric cleavage ensures weak signaling at low concentrations of CD95L and strongly accelerated activation at higher ligand concentrations, thereby contributing to precise control of apoptosis.
The SBML for this model was obtained from the BioModels database (BioModels ID: BIOMD0000000523) Biomodels notes: This model contain the equations for one "average cell" with median initial concentrations for CD95, FADD, p55, BID, PrNES_mCherry and PrER_mGFP. Figure 4A in the reference publication gives the simulation and experimental results of several cells (80 different cells). As this model is a "average cell" model, trajectories similar to that of Figure 4A has been reproduced, but for the ligand concentration of 500ng/ml (CD95L = 16.6nM (500ng/ml)). The simulation results are checked with the authors. JWS Online curation: This model was curated by reproducing the figures as described in the BioModels Notes. No additional changes were made.