In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity

Detalhes bibliográficos
Autor(a) principal: Pires, Douglas Eduardo Valente
Data de Publicação: 2016
Outros Autores: Chen, Jing, Blundell, Tom Leon, Ascher, David Benjamin
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da FIOCRUZ (ARCA)
Texto Completo: https://www.arca.fiocruz.br/handle/icict/16108
Resumo: University of Cambridge. Department of Biochemistry Sanger Building. Cambridge, CB, UK/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil.
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spelling Pires, Douglas Eduardo ValenteChen, JingBlundell, Tom LeonAscher, David Benjamin2016-10-05T19:12:58Z2016-10-05T19:12:58Z2016Pires, Douglas Eduardo Valente et al. In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity. Scientific Reports, v. 6, p. 19848, 20162045-2322https://www.arca.fiocruz.br/handle/icict/1610810.1038/srep19848engNature Publishing GroupfenotipospolymorphismsphenotypesIn silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activityinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleUniversity of Cambridge. Department of Biochemistry Sanger Building. Cambridge, CB, UK/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil.University of Cambridge. Department of Biochemistry Sanger Building. Cambridge, CB, UK.University of Cambridge. Department of Biochemistry Sanger Building. Cambridge, CB, UK.University of Cambridge. Department of Biochemistry Sanger Building. Cambridge, CB, UK.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.info:eu-repo/semantics/openAccessreponame:Repositório Institucional da FIOCRUZ (ARCA)instname:Fundação Oswaldo Cruz (FIOCRUZ)instacron:FIOCRUZLICENSElicense.txtlicense.txttext/plain; charset=utf-82991https://www.arca.fiocruz.br/bitstream/icict/16108/1/license.txt5a560609d32a3863062d77ff32785d58MD51ORIGINALVê_Pires_Douglas_In silico_CPqRR_2016.pdfVê_Pires_Douglas_In silico_CPqRR_2016.pdfapplication/pdf1657496https://www.arca.fiocruz.br/bitstream/icict/16108/2/V%c3%aa_Pires_Douglas_In%20silico_CPqRR_2016.pdfd91872702f70b3e101d3041e61a79f77MD52TEXTVê_Pires_Douglas_In silico_CPqRR_2016.pdf.txtVê_Pires_Douglas_In silico_CPqRR_2016.pdf.txtExtracted 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dc.title.pt_BR.fl_str_mv In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
title In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
spellingShingle In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
Pires, Douglas Eduardo Valente
fenotipos
polymorphisms
phenotypes
title_short In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
title_full In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
title_fullStr In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
title_full_unstemmed In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
title_sort In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
author Pires, Douglas Eduardo Valente
author_facet Pires, Douglas Eduardo Valente
Chen, Jing
Blundell, Tom Leon
Ascher, David Benjamin
author_role author
author2 Chen, Jing
Blundell, Tom Leon
Ascher, David Benjamin
author2_role author
author
author
dc.contributor.author.fl_str_mv Pires, Douglas Eduardo Valente
Chen, Jing
Blundell, Tom Leon
Ascher, David Benjamin
dc.subject.other.pt_BR.fl_str_mv fenotipos
topic fenotipos
polymorphisms
phenotypes
dc.subject.en.pt_BR.fl_str_mv polymorphisms
phenotypes
description University of Cambridge. Department of Biochemistry Sanger Building. Cambridge, CB, UK/Fundação Oswaldo Cruz. Centro de Pesquisas René Rachou. Belo Horizonte, MG, Brasil.
publishDate 2016
dc.date.accessioned.fl_str_mv 2016-10-05T19:12:58Z
dc.date.available.fl_str_mv 2016-10-05T19:12:58Z
dc.date.issued.fl_str_mv 2016
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.citation.fl_str_mv Pires, Douglas Eduardo Valente et al. In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity. Scientific Reports, v. 6, p. 19848, 2016
dc.identifier.uri.fl_str_mv https://www.arca.fiocruz.br/handle/icict/16108
dc.identifier.issn.pt_BR.fl_str_mv 2045-2322
dc.identifier.doi.none.fl_str_mv 10.1038/srep19848
identifier_str_mv Pires, Douglas Eduardo Valente et al. In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity. Scientific Reports, v. 6, p. 19848, 2016
2045-2322
10.1038/srep19848
url https://www.arca.fiocruz.br/handle/icict/16108
dc.language.iso.fl_str_mv eng
language eng
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:Repositório Institucional da FIOCRUZ (ARCA)
instname:Fundação Oswaldo Cruz (FIOCRUZ)
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