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BIOMD0000000525 - Kallenberger2014 - CD95L induced apoptosis initiated by caspase-8, CD95 HeLa cells (cis/trans-cis/trans variant)

 

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Reference Publication
Publication ID: 24619646
Kallenberger SM, Beaudouin J, Claus J, Fischer C, Sorger PK, Legewie S, Eils R.
Intra- and interdimeric caspase-8 self-cleavage controls strength and timing of CD95-induced apoptosis.
Sci Signal 2014 Mar; 7(316): ra23
1Department for Bioinformatics and Functional Genomics, Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg 69120, Germany.  [more]
Model
Original Model: BIOMD0000000525.origin
Submitter: Stefan Kallenberger
Submission ID: MODEL1403050002
Submission Date: 05 Mar 2014 18:30:55 UTC
Last Modification Date: 25 Feb 2015 12:38:56 UTC
Creation Date: 14 Mar 2014 12:40:21 UTC
Encoders:  Vijayalakshmi Chelliah
   Stefan Kallenberger
set #1
bqbiol:isVersionOf Gene Ontology apoptotic process
bqbiol:occursIn Brenda Tissue Ontology BTO:0000567
bqbiol:hasTaxon Taxonomy Homo sapiens
bqbiol:hasProperty Mathematical Modelling Ontology MAMO_0000046
Notes
Kallenberger2014 - CD95L induced apoptosis initiated by caspase-8, CD95 HeLa cells (cis/trans-cis/trans variant)

The paper describes a new approach that combines single cell and population data in the same model. The model consists of a large number of single cell models, which are fitted to single cell data. Simultaneously, ensemble averages are fitted to population data. It is assumed that the kinetics in each cell can be described with the same kinetic parameters. Therefore, cell-to-cell variability is explained by variable initial protein concentrations.

There are four variants of the model (with [CD95L]=500ng/ml = 16.6nM), i) cistrans (in CD95-HeLa cells) [ MODEL1403050000 ], ii) cistrans (in wild-type HeLa cells) [ MODEL1403050001 ], iii) cistrans-cistrans (in CD95-HeLa cells) [ MODEL1403050002 ], and iv) cistrans-cistrans (in wild-type HeLa cells) [ MODEL1403050003 ].

These model contain the equations for one "average cell" with median initial concentrations for CD95, FADD, p55, BID, PrNES_mCherry and PrER_mGFP. By integrating the model, it should be possible to obtain trajectories for PrER_mGFP, PrNES_mCherry, p43 and p18 similar as in Figure 4A (CD95-HeLa cells) and Figure 4B (wild-type HeLa cells).

This model is described in the article:

Stefan M. Kallenberger, Joël Beaudouin, Juliane Claus, Carmen Fischer, Peter K. Sorger, Stefan Legewie, and Roland Eils
11 March 2014: Vol. 7, Issue 316, p. ra23

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.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 24619646 Submission Date: 05 Mar 2014 18:30:55 UTC Last Modification Date: 25 Feb 2015 12:38:56 UTC Creation Date: 14 Mar 2014 12:40:21 UTC
Mathematical expressions
Reactions
reaction_1 reaction_2 reaction_3 reaction_4
reaction_5 reaction_6 reaction_7 reaction_8
reaction_9 reaction_10 reaction_11 reaction_12
reaction_13 reaction_14 reaction_15 reaction_16
reaction_17 reaction_18 reaction_19  
Rules
Assignment Rule (variable: CD95act)      
Physical entities
Compartments Species
cell CD95 FADD p55free
Bid PrNES_mCherry PrER_mGFP
DISC DISCp55 p30
p43 p18 p18inactive
tBid PrNES mCherry
PrER mGFP CD95L
Global parameters
kon_FADD koff_FADD kDISC kD216
kD216trans_p55 kD216trans_p43 kD374 kD374trans_p55
kD374trans_p43 kdiss_p18 kBid kD374probe
KDR KDL CD95act  
Reactions (19)
 
 reaction_1 [FADD] → [DISC];   {FADD}
 
 reaction_2 [DISC] → [FADD];   {DISC}
 
 reaction_3 [p55free] + [DISC] → [DISCp55];   {p55free} , {DISC}
 
 reaction_4 [DISCp55] → [p30];   {DISCp55}
 
 reaction_5 [DISCp55] → [p30];   {DISCp55} , {p30} , {DISCp55} , {p30}
 
 reaction_6 [DISCp55] → [p30];   {p43} , {DISCp55} , {p43}
 
 reaction_7 [p43] → [p18] + [DISC];   {p43}
 
 reaction_8 [p43] → [p18] + [DISC];   {DISCp55} , {p30} , {p43} , {DISCp55} , {p30}
 
 reaction_9 [p43] → [p18] + [DISC];   {p43} , {p43}
 
 reaction_10 [DISCp55] → [p43];   {DISCp55}
 
 reaction_11 [DISCp55] → [p43];   {DISCp55} , {p30} , {DISCp55} , {p30}
 
 reaction_12 [DISCp55] → [p43];   {p43} , {DISCp55} , {p43}
 
 reaction_13 [p30] → [p18] + [DISC];   {p30}
 
 reaction_14 [p30] → [p18] + [DISC];   {DISCp55} , {p30} , {p30} , {DISCp55}
 
 reaction_15 [p30] → [p18] + [DISC];   {p43} , {p30} , {p43}
 
 reaction_16 [p18] → [p18inactive];   {p18}
 
 reaction_17 [Bid] → [tBid];   {p43} , {p18} , {Bid} , {p43} , {p18}
 
 reaction_18 [PrNES_mCherry] → [PrNES] + [mCherry];   {p43} , {p18} , {PrNES_mCherry} , {p43} , {p18}
 
 reaction_19 [PrER_mGFP] → [PrER] + [mGFP];   {p18} , {PrER_mGFP} , {p18}
 
Rules (1)
 
 Assignment Rule (name: CD95act) CD95act = CD95^3*KDL^2*CD95L/((CD95L+KDL)*(CD95^2*KDL^2+KDR*CD95L^2+2*KDR*KDL*CD95L+KDR*KDL^2))
 
 cell Spatial dimensions: 3.0  Compartment size: 1.0
 
 CD95
Compartment: cell
Initial concentration: 116.0
 
 FADD
Compartment: cell
Initial concentration: 93.0
 
 p55free
Compartment: cell
Initial concentration: 155.0
 
 Bid
Compartment: cell
Initial concentration: 236.0
 
 PrNES_mCherry
Compartment: cell
Initial concentration: 973.0
 
 PrER_mGFP
Compartment: cell
Initial concentration: 5178.0
 
 DISC
Compartment: cell
Initial concentration: 0.0
 
 DISCp55
Compartment: cell
Initial concentration: 0.0
 
 p30
Compartment: cell
Initial concentration: 0.0
 
 p43
Compartment: cell
Initial concentration: 0.0
 
 p18
Compartment: cell
Initial concentration: 0.0
 
 p18inactive
Compartment: cell
Initial concentration: 0.0
 
 tBid
Compartment: cell
Initial concentration: 0.0
 
 PrNES
Compartment: cell
Initial concentration: 0.0
 
 mCherry
Compartment: cell
Initial concentration: 0.0
 
 PrER
Compartment: cell
Initial concentration: 0.0
 
 mGFP
Compartment: cell
Initial concentration: 0.0
 
 CD95L
Compartment: cell
Initial concentration: 16.6
 
Global Parameters (15)
 
   kon_FADD
Value: 0.00108871858684363
Constant
 
   koff_FADD
Value: 0.00130854998177646
Constant
 
   kDISC
Value: 3.64965874405544E-4
Constant
 
   kD216
Value: 0.00639775937416746
Constant
 
   kD216trans_p55
Value: 2.23246421372882E-4
Constant
 
   kD216trans_p43
Value: 5.29906975294056E-5
Constant
 
   kD374
Value: 6.44612643975149E-4
Constant
 
   kD374trans_p55
Value: 5.43518631342483E-4
Constant
 
   kD374trans_p43
Value: 0.00413530054938906
Constant
 
   kdiss_p18
Value: 0.064713651554491
Constant
 
   kBid
Value: 5.2134055139547E-4
Constant
 
   kD374probe
Value: 0.00153710001025539
Constant
 
   KDR
Value: 57.2050013008496
Constant
 
   KDL
Value: 30.0060394758199
Constant
 
   CD95act  
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000525

Curator's comment: (updated: 14 Mar 2014 12:43:12 GMT)

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.
The model was simulated using Copasi v4.12 (Build 72). The plot was generated using Gnuplot.

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