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A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins.

Cheng TM, Goehring L, Jeffery L, Lu YE, Hayles J, Novák B, Bates PA - PLoS Comput. Biol. (2012)

Bottom Line: We present two case studies: (1) interpreting systemic perturbation for mutations within the cell cycle control mechanisms (G2 to mitosis transition) for yeast; (2) phenotypic classification of neuron-related human diseases associated with mutations within the mitogen-activated protein kinase (MAPK) pathway.We show that the application of simplified mathematical models is feasible for understanding the effects of small sequence changes on cellular behavior.Furthermore, we show that the systemic impact of missense mutations can be effectively quantified as a combination of protein stability change and pathway perturbation.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.

ABSTRACT
Gauging the systemic effects of non-synonymous single nucleotide polymorphisms (nsSNPs) is an important topic in the pursuit of personalized medicine. However, it is a non-trivial task to understand how a change at the protein structure level eventually affects a cell's behavior. This is because complex information at both the protein and pathway level has to be integrated. Given that the idea of integrating both protein and pathway dynamics to estimate the systemic impact of missense mutations in proteins remains predominantly unexplored, we investigate the practicality of such an approach by formulating mathematical models and comparing them with experimental data to study missense mutations. We present two case studies: (1) interpreting systemic perturbation for mutations within the cell cycle control mechanisms (G2 to mitosis transition) for yeast; (2) phenotypic classification of neuron-related human diseases associated with mutations within the mitogen-activated protein kinase (MAPK) pathway. We show that the application of simplified mathematical models is feasible for understanding the effects of small sequence changes on cellular behavior. Furthermore, we show that the systemic impact of missense mutations can be effectively quantified as a combination of protein stability change and pathway perturbation.

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The sensitivity of the key proteins in the MAPK pathway in terms of regulating the Erk expression.(A) The reduced G2-M model. (B) The original non-reduced (Brightman and Fell) model.
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pcbi-1002738-g004: The sensitivity of the key proteins in the MAPK pathway in terms of regulating the Erk expression.(A) The reduced G2-M model. (B) The original non-reduced (Brightman and Fell) model.

Mentions: To benchmark the behavior of both the reduced and original model, a sensitivity analysis is performed over three target quantities of the reporter protein Erk (Methods section ‘Quantifying the change of expression curves’): the amplitude (maximum activation), duration (time until signal drops down to 50% of its maximum activation) and peak time (time of maximum activation). For the test, the initial concentration of the key proteins in both models is varied and their effects on controlling the target quantities of Erk is compared (the key proteins include ShcGS (Shc: Src homology and collagen domain protein), GS, Grb2 (growth factor receptor binding protein 2), SOS (son of sevenless homologous protein), Ras, Raf, Mek and Erk). As a result, the control coefficients in both models demonstrate a similar pattern across all three-target quantities (Figure 4A,B), which indicate that the reduced model does not sacrifice the overall dynamics of the original model to achieve its simpler structure.


A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins.

Cheng TM, Goehring L, Jeffery L, Lu YE, Hayles J, Novák B, Bates PA - PLoS Comput. Biol. (2012)

The sensitivity of the key proteins in the MAPK pathway in terms of regulating the Erk expression.(A) The reduced G2-M model. (B) The original non-reduced (Brightman and Fell) model.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475653&req=5

pcbi-1002738-g004: The sensitivity of the key proteins in the MAPK pathway in terms of regulating the Erk expression.(A) The reduced G2-M model. (B) The original non-reduced (Brightman and Fell) model.
Mentions: To benchmark the behavior of both the reduced and original model, a sensitivity analysis is performed over three target quantities of the reporter protein Erk (Methods section ‘Quantifying the change of expression curves’): the amplitude (maximum activation), duration (time until signal drops down to 50% of its maximum activation) and peak time (time of maximum activation). For the test, the initial concentration of the key proteins in both models is varied and their effects on controlling the target quantities of Erk is compared (the key proteins include ShcGS (Shc: Src homology and collagen domain protein), GS, Grb2 (growth factor receptor binding protein 2), SOS (son of sevenless homologous protein), Ras, Raf, Mek and Erk). As a result, the control coefficients in both models demonstrate a similar pattern across all three-target quantities (Figure 4A,B), which indicate that the reduced model does not sacrifice the overall dynamics of the original model to achieve its simpler structure.

Bottom Line: We present two case studies: (1) interpreting systemic perturbation for mutations within the cell cycle control mechanisms (G2 to mitosis transition) for yeast; (2) phenotypic classification of neuron-related human diseases associated with mutations within the mitogen-activated protein kinase (MAPK) pathway.We show that the application of simplified mathematical models is feasible for understanding the effects of small sequence changes on cellular behavior.Furthermore, we show that the systemic impact of missense mutations can be effectively quantified as a combination of protein stability change and pathway perturbation.

View Article: PubMed Central - PubMed

Affiliation: Biomolecular Modelling Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.

ABSTRACT
Gauging the systemic effects of non-synonymous single nucleotide polymorphisms (nsSNPs) is an important topic in the pursuit of personalized medicine. However, it is a non-trivial task to understand how a change at the protein structure level eventually affects a cell's behavior. This is because complex information at both the protein and pathway level has to be integrated. Given that the idea of integrating both protein and pathway dynamics to estimate the systemic impact of missense mutations in proteins remains predominantly unexplored, we investigate the practicality of such an approach by formulating mathematical models and comparing them with experimental data to study missense mutations. We present two case studies: (1) interpreting systemic perturbation for mutations within the cell cycle control mechanisms (G2 to mitosis transition) for yeast; (2) phenotypic classification of neuron-related human diseases associated with mutations within the mitogen-activated protein kinase (MAPK) pathway. We show that the application of simplified mathematical models is feasible for understanding the effects of small sequence changes on cellular behavior. Furthermore, we show that the systemic impact of missense mutations can be effectively quantified as a combination of protein stability change and pathway perturbation.

Show MeSH