Proctor, Tsiringotis, Gray, 2007

Model Status

This CellML version of the model has been checked in COR and PCEnv and the model runs to reproduce the results as shown in figure 3 of the published paper (ie. k69=0). The units have been checked and are consistent. This CellML description is deterministic, unlike the stochastic model created and preferred by the authors. Time courses produced are therefore similar to, but not exactly the same as the figures in the paper; the graphs produced by this CellML description have smooth curves since random fluctuations of the intracellular preocesses are not taken into account.

Model Structure

ABSTRACT: 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.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.

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.

The complete original paper reference is cited below:

An in silico model of the ubiquitin-proteasome system that incorporates normal homeostasis and age-related decline, Carole J. Proctor, Maria Tsirigotis and Douglas A. Gray, 2007,BMC Systems Biology, 1:17. PubMed ID: 17408507

Network diagram of the ubiquitin-proteosome model: Reactants leading to the first ubiquitination step.

Network diagram of the ubiquitin-proteosome model: reactions of chain lengthening and shortening (only shown for chains up to length four).

Network diagram of the ubiquitin-proteosome model: binding of substrate with polyubiquitin chains (of length four or more) to proteasome and chain shortening of bound substrates by DUBs which leads to release from proteasome when the chain length is less than four.

Network diagram of the ubiquitin-proteosome model: degradation of substrates by proteasome in ATP-dependent manner releasing ubiquitin for recycling.

Network diagram of the ubiquitin-proteosome model: formation of aggregated proteins, sequestering of aggregates and proteasome inhibition by aggregates.