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BIOMD0000000105 - Proctor2007 - Age related decline of proteolysis, ubiquitin-proteome system

 

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Reference Publication
Publication ID: 17408507
Proctor CJ, Tsirigotis M, Gray DA.
An in silico model of the ubiquitin-proteasome system that incorporates normal homeostasis and age-related decline.
BMC Syst Biol 2007; 1: 17
School of Clinical and Medical Sciences-Gerontology, Newcastle University, UK. c.j.proctor@ncl.ac.uk  [more]
Model
Original Model: BIOMD0000000105.xml.origin
Submitter: Carole Proctor
Submission ID: MODEL6540028317
Submission Date: 02 Apr 2007 20:45:08 UTC
Last Modification Date: 11 Aug 2014 14:38:13 UTC
Creation Date: 02 Apr 2007 09:08:41 UTC
Encoders:  Carole Proctor
   Enuo He
set #1
bqmodel:isDerivedFrom BioModels Database Proctor2005 - Actions of chaperones and their role in ageing
set #2
bqbiol:hasTaxon Taxonomy Eukaryota
set #3
bqbiol:isVersionOf Gene Ontology proteasome-mediated ubiquitin-dependent protein catabolic process
set #4
bqbiol:hasProperty Human Disease Ontology DOID:1289
Notes
Proctor2007 - Age related decline of proteolysis, ubiquitin-proteome system

This is a stochastic model of the ubiquitin-proteasome system for a generic pool of native proteins (NatP), which have a half-life of about 10 hours under normal conditions. It is assumed that these proteins are only degraded after they have lost their native structure due to a damage event. This is represented in the model by the misfolding reaction which depends on the level of reactive oxygen species (ROS) in the cell. Misfolded proteins (MisP) are first bound by an E3 ubiquitin ligase. Ubiquitin (Ub) is activated by E1 (ubiquitin-activating enzyme) and then passed to E2 (ubiquitin-conjugating enzyme). The E2 enzyme then passes the ubiquitin molecule to the E3/MisP complex with the net effect that the misfolded protein is monoubiquitinated and both E2 and E3 are released. Further ubiquitin molecules are added in a step-wise manner. When the chain of ubiquitin molecules is of length 4 or more, the polyubiquitinated misfolded protein may bind to the proteasome. The model also includes de-ubiquitinating enzymes (DUB) which cleave ubiquitin molecules from the chain in a step-wise manner. They work on chains attached to misfolded proteins both unbound and bound to the proteasomes. Misfolded proteins bound to the proteasome may be degraded releasing ubiquitin. Misfolded proteins including ubiquitinated proteins may also aggregate. Aggregates (AggP) may be sequestered (Seq_AggP) which takes them out of harm's way or they may bind to the proteasome (AggP_Proteasome). Proteasomes bound by aggregates are no longer available for protein degradation.

Figure 2 and Figure 3 has been simulated using Gillespie2.

This model is described in the article:

Proctor CJ, Tsirigotis M, Gray DA.
BMC Syst Biol 2007; 1: 17

Abstract:

BACKGROUND: The ubiquitin-proteasome system is responsible for homeostatic degradation of intact protein substrates as well as the elimination of damaged or misfolded proteins that might otherwise aggregate. During ageing there is a decline in proteasome activity and an increase in aggregated proteins. Many neurodegenerative diseases are characterised by the presence of distinctive ubiquitin-positive inclusion bodies in affected regions of the brain. These inclusions consist of insoluble, unfolded, ubiquitinated polypeptides that fail to be targeted and degraded by the proteasome. We are using a systems biology approach to try and determine the primary event in the decline in proteolytic capacity with age and whether there is in fact a vicious cycle of inhibition, with accumulating aggregates further inhibiting proteolysis, prompting accumulation of aggregates and so on. A stochastic model of the ubiquitin-proteasome system has been developed using the Systems Biology Mark-up Language (SBML). Simulations are carried out on the BASIS (Biology of Ageing e-Science Integration and Simulation) system and the model output is compared to experimental data wherein levels of ubiquitin and ubiquitinated substrates are monitored in cultured cells under various conditions. The model can be used to predict the effects of different experimental procedures such as inhibition of the proteasome or shutting down the enzyme cascade responsible for ubiquitin conjugation. RESULTS: The model output shows good agreement with experimental data under a number of different conditions. However, our model predicts that monomeric ubiquitin pools are always depleted under conditions of proteasome inhibition, whereas experimental data show that monomeric pools were depleted in IMR-90 cells but not in ts20 cells, suggesting that cell lines vary in their ability to replenish ubiquitin pools and there is the need to incorporate ubiquitin turnover into the model. Sensitivity analysis of the model revealed which parameters have an important effect on protein turnover and aggregation kinetics. CONCLUSION: We have developed a model of the ubiquitin-proteasome system using an iterative approach of model building and validation against experimental data. Using SBML to encode the model ensures that it can be easily modified and extended as more data become available. Important aspects to be included in subsequent models are details of ubiquitin turnover, models of autophagy, the inclusion of a pool of short-lived proteins and further details of the aggregation process.

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: 17408507 Submission Date: 02 Apr 2007 20:45:08 UTC Last Modification Date: 11 Aug 2014 14:38:13 UTC Creation Date: 02 Apr 2007 09:08:41 UTC
Mathematical expressions
Reactions
ProteinSynthesis Misfolding Refolding MisPE3Binding
MisPE3Release E1UbBinding E2UbBinding Monoubiquitination
Polyubiquitination1 Polyubiquitination2 Polyubiquitination3 Polyubiquitination4
Polyubiquitination5 Polyubiquitination6 Polyubiquitination7 Deubiqutination1
Deubiqutination2 Deubiqutination3 Deubiqutination4 Deubiqutination5
Deubiqutination6 Deubiqutination7 Deubiqutination8 ProteasomeBinding1
ProteasomeBinding2 ProteasomeBinding3 ProteasomeBinding4 ProteasomeBinding5
DeubiquitinationBoundMisP5 DeubiquitinationBoundMisP4 DeubiquitinationBoundMisP3 DeubiquitinationBoundMisP2
DeubiquitinationBoundMisP1 ProteasomeActivity1 ProteasomeActivity2 ProteasomeActivity3
ProteasomeActivity4 ProteasomeActivity5 Aggregation1 Aggregation2
Aggregation3 Aggregation4 Aggregation5 Aggregation6
Aggregation7 Aggregation8 Aggregation9 Aggregation10
Aggregation11 Aggregation12 Aggregation13 Aggregation14
Aggregation15 Aggregation16 Aggregation17 Aggregation18
Aggregation19 Aggregation20 Aggregation21 Aggregation22
Aggregation23 Aggregation24 Aggregation25 Aggregation26
Aggregation27 Aggregation28 Aggregation29 Aggregation30
Aggregation31 Aggregation32 Aggregation33 Aggregation34
Aggregation35 Aggregation36 Aggregation37 Aggregation38
Aggregation39 Aggregation40 Aggregation41 Aggregation42
Aggregation43 Aggregation44 Aggregation45 Aggregation46
Aggregation47 Aggregation48 Aggregation49 Aggregation50
Aggregation51 Aggregation52 Aggregation53 Aggregation54
SequesteringOfAggregates ProteasomeInhibtion    
Physical entities
Compartments Species
cytosol NatP MisP Ub
E1 E2 E3
DUB Proteasome ROS
E1_Ub E2_Ub E3_MisP
MisP_Ub MisP_Ub2 MisP_Ub3
MisP_Ub4 MisP_Ub5 MisP_Ub6
MisP_Ub7 MisP_Ub8 MisP_Ub4_Proteasome
MisP_Ub5_Proteasome MisP_Ub6_Proteasome MisP_Ub7_Proteasome
MisP_Ub8_Proteasome ATP ADP
AMP Source degUb4
degUb5 degUb6 degUb7
degUb8 totMisP refNatP
AggP SeqAggP AggP_Proteasome
Global parameters
k1 k2 k3 k61
k61r k62 k63 k64
k65 k66 k67 k68
k69 k71 k72 k73
k74      
Reactions (94)
 
 ProteinSynthesis [Source] → [NatP];  
 
 Misfolding [NatP] + [ROS] → [MisP] + [ROS] + [totMisP];  
 
 Refolding [MisP] → [NatP] + [refNatP];  
 
 MisPE3Binding [MisP] + [E3] → [E3_MisP];  
 
 MisPE3Release [E3_MisP] → [MisP] + [E3];  
 
 E1UbBinding [E1] + [Ub] + [ATP] → [E1_Ub] + [AMP];  
 
 E2UbBinding [E2] + [E1_Ub] → [E2_Ub] + [E1];  
 
 Monoubiquitination [E2_Ub] + [E3_MisP] → [MisP_Ub] + [E2] + [E3];  
 
 Polyubiquitination1 [MisP_Ub] + [E2_Ub] → [MisP_Ub2] + [E2];  
 
 Polyubiquitination2 [MisP_Ub2] + [E2_Ub] → [MisP_Ub3] + [E2];  
 
 Polyubiquitination3 [MisP_Ub3] + [E2_Ub] → [MisP_Ub4] + [E2];  
 
 Polyubiquitination4 [MisP_Ub4] + [E2_Ub] → [MisP_Ub5] + [E2];  
 
 Polyubiquitination5 [MisP_Ub5] + [E2_Ub] → [MisP_Ub6] + [E2];  
 
 Polyubiquitination6 [MisP_Ub6] + [E2_Ub] → [MisP_Ub7] + [E2];  
 
 Polyubiquitination7 [MisP_Ub7] + [E2_Ub] → [MisP_Ub8] + [E2];  
 
 Deubiqutination1 [MisP_Ub8] + [DUB] → [MisP_Ub7] + [DUB] + [Ub];  
 
 Deubiqutination2 [MisP_Ub7] + [DUB] → [MisP_Ub6] + [DUB] + [Ub];  
 
 Deubiqutination3 [MisP_Ub6] + [DUB] → [MisP_Ub5] + [DUB] + [Ub];  
 
 Deubiqutination4 [MisP_Ub5] + [DUB] → [MisP_Ub4] + [DUB] + [Ub];  
 
 Deubiqutination5 [MisP_Ub4] + [DUB] → [MisP_Ub3] + [DUB] + [Ub];  
 
 Deubiqutination6 [MisP_Ub3] + [DUB] → [MisP_Ub2] + [DUB] + [Ub];  
 
 Deubiqutination7 [MisP_Ub2] + [DUB] → [MisP_Ub] + [DUB] + [Ub];  
 
 Deubiqutination8 [MisP_Ub] + [DUB] → [MisP] + [DUB] + [Ub];  
 
 ProteasomeBinding1 [MisP_Ub4] + [Proteasome] → [MisP_Ub4_Proteasome];  
 
 ProteasomeBinding2 [MisP_Ub5] + [Proteasome] → [MisP_Ub5_Proteasome];  
 
 ProteasomeBinding3 [MisP_Ub6] + [Proteasome] → [MisP_Ub6_Proteasome];  
 
 ProteasomeBinding4 [MisP_Ub7] + [Proteasome] → [MisP_Ub7_Proteasome];  
 
 ProteasomeBinding5 [MisP_Ub8] + [Proteasome] → [MisP_Ub8_Proteasome];  
 
 DeubiquitinationBoundMisP5 [MisP_Ub8_Proteasome] + [DUB] → [MisP_Ub7_Proteasome] + [Ub] + [DUB];  
 
 DeubiquitinationBoundMisP4 [MisP_Ub7_Proteasome] + [DUB] → [MisP_Ub6_Proteasome] + [Ub] + [DUB];  
 
 DeubiquitinationBoundMisP3 [MisP_Ub6_Proteasome] + [DUB] → [MisP_Ub5_Proteasome] + [Ub] + [DUB];  
 
 DeubiquitinationBoundMisP2 [MisP_Ub5_Proteasome] + [DUB] → [MisP_Ub4_Proteasome] + [Ub] + [DUB];  
 
 DeubiquitinationBoundMisP1 [MisP_Ub4_Proteasome] + [DUB] → [MisP_Ub3] + [Proteasome] + [Ub] + [DUB];  
 
 ProteasomeActivity1 [MisP_Ub4_Proteasome] + [ATP] → 4.0 × [Ub] + [Proteasome] + [ADP] + [degUb4];  
 
 ProteasomeActivity2 [MisP_Ub5_Proteasome] + [ATP] → 5.0 × [Ub] + [Proteasome] + [ADP] + [degUb5];  
 
 ProteasomeActivity3 [MisP_Ub6_Proteasome] + [ATP] → 6.0 × [Ub] + [Proteasome] + [ADP] + [degUb6];  
 
 ProteasomeActivity4 [MisP_Ub7_Proteasome] + [ATP] → 7.0 × [Ub] + [Proteasome] + [ADP] + [degUb7];  
 
 ProteasomeActivity5 [MisP_Ub8_Proteasome] + [ATP] → 8.0 × [Ub] + [Proteasome] + [ADP] + [degUb8];  
 
 Aggregation1 2.0 × [MisP] → [AggP];  
 
 Aggregation2 [MisP] + [AggP] → 2.0 × [AggP];  
 
 Aggregation3 2.0 × [MisP_Ub] → [AggP];  
 
 Aggregation4 2.0 × [MisP_Ub2] → [AggP];  
 
 Aggregation5 2.0 × [MisP_Ub3] → [AggP];  
 
 Aggregation6 2.0 × [MisP_Ub4] → [AggP];  
 
 Aggregation7 2.0 × [MisP_Ub5] → [AggP];  
 
 Aggregation8 2.0 × [MisP_Ub6] → [AggP];  
 
 Aggregation9 2.0 × [MisP_Ub7] → [AggP];  
 
 Aggregation10 2.0 × [MisP_Ub8] → [AggP];  
 
 Aggregation11 [MisP_Ub] + [MisP] → [AggP];  
 
 Aggregation12 [MisP_Ub2] + [MisP] → [AggP];  
 
 Aggregation13 [MisP_Ub3] + [MisP] → [AggP];  
 
 Aggregation14 [MisP_Ub4] + [MisP] → [AggP];  
 
 Aggregation15 [MisP_Ub5] + [MisP] → [AggP];  
 
 Aggregation16 [MisP_Ub6] + [MisP] → [AggP];  
 
 Aggregation17 [MisP_Ub7] + [MisP] → [AggP];  
 
 Aggregation18 [MisP_Ub8] + [MisP] → [AggP];  
 
 Aggregation19 [MisP_Ub] + [AggP] → 2.0 × [AggP];  
 
 Aggregation20 [MisP_Ub2] + [AggP] → 2.0 × [AggP];  
 
 Aggregation21 [MisP_Ub3] + [AggP] → 2.0 × [AggP];  
 
 Aggregation22 [MisP_Ub4] + [AggP] → 2.0 × [AggP];  
 
 Aggregation23 [MisP_Ub5] + [AggP] → 2.0 × [AggP];  
 
 Aggregation24 [MisP_Ub6] + [AggP] → 2.0 × [AggP];  
 
 Aggregation25 [MisP_Ub7] + [AggP] → 2.0 × [AggP];  
 
 Aggregation26 [MisP_Ub8] + [AggP] → 2.0 × [AggP];  
 
 Aggregation27 [MisP_Ub] + [MisP_Ub2] → [AggP];  
 
 Aggregation28 [MisP_Ub] + [MisP_Ub3] → [AggP];  
 
 Aggregation29 [MisP_Ub] + [MisP_Ub4] → [AggP];  
 
 Aggregation30 [MisP_Ub] + [MisP_Ub5] → [AggP];  
 
 Aggregation31 [MisP_Ub] + [MisP_Ub6] → [AggP];  
 
 Aggregation32 [MisP_Ub] + [MisP_Ub7] → [AggP];  
 
 Aggregation33 [MisP_Ub] + [MisP_Ub8] → [AggP];  
 
 Aggregation34 [MisP_Ub2] + [MisP_Ub3] → [AggP];  
 
 Aggregation35 [MisP_Ub2] + [MisP_Ub4] → [AggP];  
 
 Aggregation36 [MisP_Ub2] + [MisP_Ub5] → [AggP];  
 
 Aggregation37 [MisP_Ub2] + [MisP_Ub6] → [AggP];  
 
 Aggregation38 [MisP_Ub2] + [MisP_Ub7] → [AggP];  
 
 Aggregation39 [MisP_Ub2] + [MisP_Ub8] → [AggP];  
 
 Aggregation40 [MisP_Ub3] + [MisP_Ub4] → [AggP];  
 
 Aggregation41 [MisP_Ub3] + [MisP_Ub5] → [AggP];  
 
 Aggregation42 [MisP_Ub3] + [MisP_Ub6] → [AggP];  
 
 Aggregation43 [MisP_Ub3] + [MisP_Ub7] → [AggP];  
 
 Aggregation44 [MisP_Ub3] + [MisP_Ub8] → [AggP];  
 
 Aggregation45 [MisP_Ub4] + [MisP_Ub5] → [AggP];  
 
 Aggregation46 [MisP_Ub4] + [MisP_Ub6] → [AggP];  
 
 Aggregation47 [MisP_Ub4] + [MisP_Ub7] → [AggP];  
 
 Aggregation48 [MisP_Ub4] + [MisP_Ub8] → [AggP];  
 
 Aggregation49 [MisP_Ub5] + [MisP_Ub6] → [AggP];  
 
 Aggregation50 [MisP_Ub5] + [MisP_Ub7] → [AggP];  
 
 Aggregation51 [MisP_Ub5] + [MisP_Ub8] → [AggP];  
 
 Aggregation52 [MisP_Ub6] + [MisP_Ub7] → [AggP];  
 
 Aggregation53 [MisP_Ub6] + [MisP_Ub8] → [AggP];  
 
 Aggregation54 [MisP_Ub7] + [MisP_Ub8] → [AggP];  
 
 SequesteringOfAggregates [AggP] → [SeqAggP];  
 
 ProteasomeInhibtion [AggP] + [Proteasome] → [AggP_Proteasome];  
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
   NatP
Compartment: cytosol
Initial amount: 500.0
 
   MisP
Compartment: cytosol
Initial amount: 0.0
 
 Ub
Compartment: cytosol
Initial amount: 500.0
 
 E1
Compartment: cytosol
Initial amount: 100.0
 
 E2
Compartment: cytosol
Initial amount: 100.0
 
 E3
Compartment: cytosol
Initial amount: 100.0
 
 DUB
Compartment: cytosol
Initial amount: 200.0
 
 Proteasome
Compartment: cytosol
Initial amount: 100.0
 
 ROS
Compartment: cytosol
Initial amount: 10.0
 
 E1_Ub
Compartment: cytosol
Initial amount: 0.0
 
 E2_Ub
Compartment: cytosol
Initial amount: 0.0
 
   E3_MisP
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub2
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub3
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub4
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub5
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub6
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub7
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub8
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub4_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub5_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub6_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub7_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
   MisP_Ub8_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
 ATP
Compartment: cytosol
Initial amount: 10000.0
Constant
 
 ADP
Compartment: cytosol
Initial amount: 1000.0
Constant
 
 AMP
Compartment: cytosol
Initial amount: 1000.0
Constant
 
   Source
Compartment: cytosol
Initial amount: 1.0
Constant
 
   degUb4
Compartment: cytosol
Initial amount: 0.0
 
   degUb5
Compartment: cytosol
Initial amount: 0.0
 
   degUb6
Compartment: cytosol
Initial amount: 0.0
 
   degUb7
Compartment: cytosol
Initial amount: 0.0
 
   degUb8
Compartment: cytosol
Initial amount: 0.0
 
   totMisP
Compartment: cytosol
Initial amount: 0.0
 
   refNatP
Compartment: cytosol
Initial amount: 0.0
 
   AggP
Compartment: cytosol
Initial amount: 0.0
 
   SeqAggP
Compartment: cytosol
Initial amount: 0.0
 
   AggP_Proteasome
Compartment: cytosol
Initial amount: 0.0
 
Global Parameters (17)
 
   k1
Value: 0.01
Constant
 
   k2
Value: 2.0E-6
Constant
 
   k3
Value: 4.0E-6
Constant
 
   k61
Value: 1.7E-5
Constant
 
   k61r
Value: 2.0E-4
Constant
 
   k62
Value: 2.0E-4
Constant
 
   k63
Value: 0.0010
Constant
 
   k64
Value: 0.0010
Constant
 
   k65
Value: 0.01
Constant
 
   k66
Value: 1.0E-5
Constant
 
   k67
Value: 1.0E-5
Constant
 
   k68
Value: 1.0E-5
Constant
 
 k69
Constant
 
   k71
Value: 1.0E-8
Constant
 
   k72
Value: 1.0E-8
Constant
 
   k73
Value: 0.0010
Constant
 
   k74
Value: 1.0E-5
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000105

Curator's comment: (updated: 02 Apr 2007 19:58:29 BST)

Figure3 (i) (iii) (v) have been reproduced by Gillespie2.

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