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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 mutations studied in the MAPK model.(A) A scheme of the MAPK pathway. (B) Mapping the mutations onto the three dimensional structures; mutations located at or close to the active site are colored in blue, otherwise colored in red.
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pcbi-1002738-g003: The mutations studied in the MAPK model.(A) A scheme of the MAPK pathway. (B) Mapping the mutations onto the three dimensional structures; mutations located at or close to the active site are colored in blue, otherwise colored in red.

Mentions: The MAPK pathway plays an essential role in cell survival, proliferation, differentiation and development (Figure 3A). Its three-tier MAPK cascade, i.e. Raf-Mek-Erk, is a highly conserved systemic structure that regulates the switch-like behavior of the pathway's signal transduction mechanism [22]. The important features of this cascade manifest themselves as representatives to evaluate the behavior of the parental pathway, and previous studies of the human MAPK pathway have shown analytical results which support this [23], [24]. To explore the effectiveness of a model that focuses on the dynamics of the three-tier structure, a reduced model is constructed here based on previous work that simulated the signaling cascade from the epidermal growth factor (EGF) receptor to the Erk reporter protein [25]. By omitting redundant terms whose removal has little effect on the expression curve of the downstream protein Erk, a set of succinct ODEs is derived as shown in Table 4 (the derivation is presented in Text S3).


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 mutations studied in the MAPK model.(A) A scheme of the MAPK pathway. (B) Mapping the mutations onto the three dimensional structures; mutations located at or close to the active site are colored in blue, otherwise colored in red.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1002738-g003: The mutations studied in the MAPK model.(A) A scheme of the MAPK pathway. (B) Mapping the mutations onto the three dimensional structures; mutations located at or close to the active site are colored in blue, otherwise colored in red.
Mentions: The MAPK pathway plays an essential role in cell survival, proliferation, differentiation and development (Figure 3A). Its three-tier MAPK cascade, i.e. Raf-Mek-Erk, is a highly conserved systemic structure that regulates the switch-like behavior of the pathway's signal transduction mechanism [22]. The important features of this cascade manifest themselves as representatives to evaluate the behavior of the parental pathway, and previous studies of the human MAPK pathway have shown analytical results which support this [23], [24]. To explore the effectiveness of a model that focuses on the dynamics of the three-tier structure, a reduced model is constructed here based on previous work that simulated the signaling cascade from the epidermal growth factor (EGF) receptor to the Erk reporter protein [25]. By omitting redundant terms whose removal has little effect on the expression curve of the downstream protein Erk, a set of succinct ODEs is derived as shown in Table 4 (the derivation is presented in Text S3).

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