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

Panchenko, A.R.R., Cheng, T.M.K., Goehring, L. ORCID: 0000-0002-3858-7295, Jeffery, L., Lu, Y.E., Hayles, J., Novák, B. and Bates, P.A., 2012. A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins. PLOS Computational Biology, 8 (10), e1002738. ISSN 1553-7358

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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.

Item Type: Journal article
Publication Title: PLOS Computational Biology
Creators: Panchenko, A.R.R., Cheng, T.M.K., Goehring, L., Jeffery, L., Lu, Y.E., Hayles, J., Novák, B. and Bates, P.A.
Publisher: Public Library of Science
Date: 18 October 2012
Volume: 8
Number: 10
ISSN: 1553-7358
Identifiers:
NumberType
10.1371/journal.pcbi.1002738DOI
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 05 Sep 2016 08:13
Last Modified: 16 Oct 2017 15:49
URI: http://irep.ntu.ac.uk/id/eprint/28370

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