In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
Nature Publishing Group
MetadataShow full item record
Pires, D. E., Chen, J., Blundell, T., & Ascher, D. (2016). In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity. Scientific Reports, 6 (19848)https://doi.org/10.1038/srep19848
Despite interest in associating polymorphisms with clinical or experimental phenotypes, functional interpretation of mutation data has lagged behind generation of data from modern high-throughput techniques and the accurate prediction of the molecular impact of a mutation remains a non-trivial task. We present here an integrated knowledge-driven computational workflow designed to evaluate the effects of experimental and disease missense mutations on protein structure and interactions. We exemplify its application with analyses of saturation mutagenesis of DBR1 and Gal4 and show that the experimental phenotypes for over 80% of the mutations correlate well with predicted effects of mutations on protein stability and RNA binding affinity. We also show that analysis of mutations in VHL using our workflow provides valuable insights into the effects of mutations, and their links to the risk of developing renal carcinoma. Taken together the analyses of the three examples demonstrate that structural bioinformatics tools, when applied in a systematic, integrated way, can rapidly analyse a given system to provide a powerful approach for predicting structural and functional effects of thousands of mutations in order to reveal molecular mechanisms leading to a phenotype.
Newton Fund RCUK-CONFAP Grant awarded by The Medical Research Council (MRC) and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) [to D.E.V.P, T.L.B. and D.B.A.]. Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and René Rachou Research Center (CPqRR/FIOCRUZ Minas), Brazil [to D.E.V.P.]; NHMRC CJ Martin Fellowship [APP1072476 to D.B.A.]; University of Cambridge and The Wellcome Trust for facilities and support [to T.L.B.]. Funding for open access charge: The Wellcome Trust.
Medical Research Council (MR/N501864/1)
External DOI: https://doi.org/10.1038/srep19848
This record's URL: https://www.repository.cam.ac.uk/handle/1810/252917
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/