Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example

Autores
Alibés, Andreu; Nadra, Alejandro Daniel; De Masi, Federico; Bulyk, Martha L.; Serrano, Luis; Stricher, François
Año de publicación
2010
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Quite often a single or a combination of protein mutations is linked to specific diseases. However, distinguishing from sequence information which mutations have real effects in the protein's function is not trivial. Protein design tools are commonly used to explain mutations that affect protein stability, or protein-protein interaction, but not for mutations that could affect protein-DNA binding. Here, we used the protein design algorithm FoldX to model all known missense mutations in the paired box domain of Pax6, a highly conserved transcription factor involved in eye development and in several diseases such as aniridia. The validity of FoldX to deal with protein-DNA interactions was demonstrated by showing that high levels of accuracy can be achieved for mutations affecting these interactions. Also we showed that protein-design algorithms can accurately reproduce experimental DNA-binding logos. We conclude that 88 of the Pax6 mutations can be linked to changes in intrinsic stability (77) and/or to its capabilities to bind DNA (30). Our study emphasizes the importance of structure-based analysis to understand the molecular basis of diseases and shows that protein-DNA interactions can be analyzed to the same level of accuracy as protein stability, or protein-protein interactions.
Fil: Alibés, Andreu. Universitat Pompeu Fabra; España
Fil: Nadra, Alejandro Daniel. Universitat Pompeu Fabra; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: De Masi, Federico. Brigham and Women's Hospital; Estados Unidos
Fil: Bulyk, Martha L.. Brigham and Women's Hospital; Estados Unidos. Harvard Medical School; Estados Unidos
Fil: Serrano, Luis. Universitat Pompeu Fabra; España. Institució Catalana de Recerca i Estudis Avancats; España
Fil: Stricher, François. Universitat Pompeu Fabra; España
Materia
Structure-based prediction
Protein-DNA
pax-6
FoldX
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/68053
Acceder
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network_name_str CONICET Digital (CONICET)
spelling Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 exampleAlibés, AndreuNadra, Alejandro DanielDe Masi, FedericoBulyk, Martha L.Serrano, LuisStricher, FrançoisStructure-based predictionProtein-DNApax-6FoldXhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Quite often a single or a combination of protein mutations is linked to specific diseases. However, distinguishing from sequence information which mutations have real effects in the protein's function is not trivial. Protein design tools are commonly used to explain mutations that affect protein stability, or protein-protein interaction, but not for mutations that could affect protein-DNA binding. Here, we used the protein design algorithm FoldX to model all known missense mutations in the paired box domain of Pax6, a highly conserved transcription factor involved in eye development and in several diseases such as aniridia. The validity of FoldX to deal with protein-DNA interactions was demonstrated by showing that high levels of accuracy can be achieved for mutations affecting these interactions. Also we showed that protein-design algorithms can accurately reproduce experimental DNA-binding logos. We conclude that 88 of the Pax6 mutations can be linked to changes in intrinsic stability (77) and/or to its capabilities to bind DNA (30). Our study emphasizes the importance of structure-based analysis to understand the molecular basis of diseases and shows that protein-DNA interactions can be analyzed to the same level of accuracy as protein stability, or protein-protein interactions.Fil: Alibés, Andreu. Universitat Pompeu Fabra; EspañaFil: Nadra, Alejandro Daniel. Universitat Pompeu Fabra; España. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: De Masi, Federico. Brigham and Women's Hospital; Estados UnidosFil: Bulyk, Martha L.. Brigham and Women's Hospital; Estados Unidos. Harvard Medical School; Estados UnidosFil: Serrano, Luis. Universitat Pompeu Fabra; España. Institució Catalana de Recerca i Estudis Avancats; EspañaFil: Stricher, François. Universitat Pompeu Fabra; EspañaOxford University Press2010-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/68053Alibés, Andreu; Nadra, Alejandro Daniel; De Masi, Federico; Bulyk, Martha L.; Serrano, Luis; et al.; Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example; Oxford University Press; Nucleic Acids Research; 38; 21; 11-2010; 7422-74310305-10481362-4962CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1093/nar/gkq683info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/nar/article/38/21/7422/2411827info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:41:27Zoai:ri.conicet.gov.ar:11336/68053instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:41:27.637CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example
title Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example
spellingShingle Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example
Alibés, Andreu
Structure-based prediction
Protein-DNA
pax-6
FoldX
title_short Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example
title_full Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example
title_fullStr Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example
title_full_unstemmed Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example
title_sort Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example
dc.creator.none.fl_str_mv Alibés, Andreu
Nadra, Alejandro Daniel
De Masi, Federico
Bulyk, Martha L.
Serrano, Luis
Stricher, François
author Alibés, Andreu
author_facet Alibés, Andreu
Nadra, Alejandro Daniel
De Masi, Federico
Bulyk, Martha L.
Serrano, Luis
Stricher, François
author_role author
author2 Nadra, Alejandro Daniel
De Masi, Federico
Bulyk, Martha L.
Serrano, Luis
Stricher, François
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Structure-based prediction
Protein-DNA
pax-6
FoldX
topic Structure-based prediction
Protein-DNA
pax-6
FoldX
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Quite often a single or a combination of protein mutations is linked to specific diseases. However, distinguishing from sequence information which mutations have real effects in the protein's function is not trivial. Protein design tools are commonly used to explain mutations that affect protein stability, or protein-protein interaction, but not for mutations that could affect protein-DNA binding. Here, we used the protein design algorithm FoldX to model all known missense mutations in the paired box domain of Pax6, a highly conserved transcription factor involved in eye development and in several diseases such as aniridia. The validity of FoldX to deal with protein-DNA interactions was demonstrated by showing that high levels of accuracy can be achieved for mutations affecting these interactions. Also we showed that protein-design algorithms can accurately reproduce experimental DNA-binding logos. We conclude that 88 of the Pax6 mutations can be linked to changes in intrinsic stability (77) and/or to its capabilities to bind DNA (30). Our study emphasizes the importance of structure-based analysis to understand the molecular basis of diseases and shows that protein-DNA interactions can be analyzed to the same level of accuracy as protein stability, or protein-protein interactions.
Fil: Alibés, Andreu. Universitat Pompeu Fabra; España
Fil: Nadra, Alejandro Daniel. Universitat Pompeu Fabra; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: De Masi, Federico. Brigham and Women's Hospital; Estados Unidos
Fil: Bulyk, Martha L.. Brigham and Women's Hospital; Estados Unidos. Harvard Medical School; Estados Unidos
Fil: Serrano, Luis. Universitat Pompeu Fabra; España. Institució Catalana de Recerca i Estudis Avancats; España
Fil: Stricher, François. Universitat Pompeu Fabra; España
description Quite often a single or a combination of protein mutations is linked to specific diseases. However, distinguishing from sequence information which mutations have real effects in the protein's function is not trivial. Protein design tools are commonly used to explain mutations that affect protein stability, or protein-protein interaction, but not for mutations that could affect protein-DNA binding. Here, we used the protein design algorithm FoldX to model all known missense mutations in the paired box domain of Pax6, a highly conserved transcription factor involved in eye development and in several diseases such as aniridia. The validity of FoldX to deal with protein-DNA interactions was demonstrated by showing that high levels of accuracy can be achieved for mutations affecting these interactions. Also we showed that protein-design algorithms can accurately reproduce experimental DNA-binding logos. We conclude that 88 of the Pax6 mutations can be linked to changes in intrinsic stability (77) and/or to its capabilities to bind DNA (30). Our study emphasizes the importance of structure-based analysis to understand the molecular basis of diseases and shows that protein-DNA interactions can be analyzed to the same level of accuracy as protein stability, or protein-protein interactions.
publishDate 2010
dc.date.none.fl_str_mv 2010-11
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/68053
Alibés, Andreu; Nadra, Alejandro Daniel; De Masi, Federico; Bulyk, Martha L.; Serrano, Luis; et al.; Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example; Oxford University Press; Nucleic Acids Research; 38; 21; 11-2010; 7422-7431
0305-1048
1362-4962
CONICET Digital
CONICET
url http://hdl.handle.net/11336/68053
identifier_str_mv Alibés, Andreu; Nadra, Alejandro Daniel; De Masi, Federico; Bulyk, Martha L.; Serrano, Luis; et al.; Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: The Pax6 example; Oxford University Press; Nucleic Acids Research; 38; 21; 11-2010; 7422-7431
0305-1048
1362-4962
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1093/nar/gkq683
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/nar/article/38/21/7422/2411827
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844614445559447552
score 13.070432

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