Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatinbinding protein involved in neuronal development and maturation. Loss-of-function mutations in MeCP2 result in Rett syndrome (RTT), a neurodevelopmental disorder that is the main cause of mental retardation in females...

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Autores: Ortega-Alarcon, David|||0000-0003-1885-4365, Claveria-Gimeno, Rafael, Vega, Sonia, Jorge-Torres, Olga Caridad|||0000-0002-1219-8865, Esteller, M.|||0000-0003-4490-6093, Abián, Olga|||0000-0001-5664-1729, Velázquez-Campoy, Adrián|||0000-0001-5702-4538
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:236604
Acceso en línea:https://ddd.uab.cat/record/236604
https://dx.doi.org/urn:doi:10.3390/biom10111533
Access Level:acceso abierto
Palabra clave:Methyl-CpG-binding protein 2 (MeCP2)
Rett syndrome
Intrinsically disordered protein (IDP)
Isothermal titration calorimetry (ITC)
Protein stability
Protein-DNA interaction
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spelling Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2Ortega-Alarcon, David|||0000-0003-1885-4365Claveria-Gimeno, RafaelVega, SoniaJorge-Torres, Olga Caridad|||0000-0002-1219-8865Esteller, M.|||0000-0003-4490-6093Abián, Olga|||0000-0001-5664-1729Velázquez-Campoy, Adrián|||0000-0001-5702-4538Methyl-CpG-binding protein 2 (MeCP2)Rett syndromeIntrinsically disordered protein (IDP)Isothermal titration calorimetry (ITC)Protein stabilityProtein-DNA interactionMethyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatinbinding protein involved in neuronal development and maturation. Loss-of-function mutations in MeCP2 result in Rett syndrome (RTT), a neurodevelopmental disorder that is the main cause of mental retardation in females. MeCP2 is an intrinsically disordered protein (IDP) constituted by six domains. Two domains are the main responsible elements for DNA binding (methyl-CpG binding domain, MBD) and recruitment of gene transcription/silencing machinery (transcription repressor domain, TRD). These two domains concentrate most of the RTT-associated mutations. R106W and R133C are associated with severe and mild RTT phenotype, respectively. We have performed a comprehensive characterization of the structural and functional impact of these substitutions at molecular level. Because we have previously shown that the MBD-flanking disordered domains (Nterminal domain, NTD, and intervening domain, ID) exert a considerable influence on the structural and functional features of the MBD (Claveria-Gimeno, R. et al. Sci Rep. 2017, 7, 41635), here we report the biophysical study of the influence of the protein scaffold on the structural and functional effect induced by these two RTT-associated mutations. These results represent an example of how a given mutation may show different effects (sometimes opposing effects) depending on the molecular context.Universitat Autònoma de Barcelona 22020-01-0120202020-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/236604https://dx.doi.org/urn:doi:10.3390/biom10111533reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Economía y Competitividad https://doi.org/10.13039/501100003329 BFU2016-78232-PInstituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI15-00663Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18-00349Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 BES-2017-080739Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CPII13-00017open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:2366042026-06-06T12:50:31Z
dc.title.none.fl_str_mv Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2
title Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2
spellingShingle Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2
Ortega-Alarcon, David|||0000-0003-1885-4365
Methyl-CpG-binding protein 2 (MeCP2)
Rett syndrome
Intrinsically disordered protein (IDP)
Isothermal titration calorimetry (ITC)
Protein stability
Protein-DNA interaction
title_short Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2
title_full Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2
title_fullStr Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2
title_full_unstemmed Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2
title_sort Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2
dc.creator.none.fl_str_mv Ortega-Alarcon, David|||0000-0003-1885-4365
Claveria-Gimeno, Rafael
Vega, Sonia
Jorge-Torres, Olga Caridad|||0000-0002-1219-8865
Esteller, M.|||0000-0003-4490-6093
Abián, Olga|||0000-0001-5664-1729
Velázquez-Campoy, Adrián|||0000-0001-5702-4538
author Ortega-Alarcon, David|||0000-0003-1885-4365
author_facet Ortega-Alarcon, David|||0000-0003-1885-4365
Claveria-Gimeno, Rafael
Vega, Sonia
Jorge-Torres, Olga Caridad|||0000-0002-1219-8865
Esteller, M.|||0000-0003-4490-6093
Abián, Olga|||0000-0001-5664-1729
Velázquez-Campoy, Adrián|||0000-0001-5702-4538
author_role author
author2 Claveria-Gimeno, Rafael
Vega, Sonia
Jorge-Torres, Olga Caridad|||0000-0002-1219-8865
Esteller, M.|||0000-0003-4490-6093
Abián, Olga|||0000-0001-5664-1729
Velázquez-Campoy, Adrián|||0000-0001-5702-4538
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universitat Autònoma de Barcelona
dc.subject.none.fl_str_mv Methyl-CpG-binding protein 2 (MeCP2)
Rett syndrome
Intrinsically disordered protein (IDP)
Isothermal titration calorimetry (ITC)
Protein stability
Protein-DNA interaction
topic Methyl-CpG-binding protein 2 (MeCP2)
Rett syndrome
Intrinsically disordered protein (IDP)
Isothermal titration calorimetry (ITC)
Protein stability
Protein-DNA interaction
description Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatinbinding protein involved in neuronal development and maturation. Loss-of-function mutations in MeCP2 result in Rett syndrome (RTT), a neurodevelopmental disorder that is the main cause of mental retardation in females. MeCP2 is an intrinsically disordered protein (IDP) constituted by six domains. Two domains are the main responsible elements for DNA binding (methyl-CpG binding domain, MBD) and recruitment of gene transcription/silencing machinery (transcription repressor domain, TRD). These two domains concentrate most of the RTT-associated mutations. R106W and R133C are associated with severe and mild RTT phenotype, respectively. We have performed a comprehensive characterization of the structural and functional impact of these substitutions at molecular level. Because we have previously shown that the MBD-flanking disordered domains (Nterminal domain, NTD, and intervening domain, ID) exert a considerable influence on the structural and functional features of the MBD (Claveria-Gimeno, R. et al. Sci Rep. 2017, 7, 41635), here we report the biophysical study of the influence of the protein scaffold on the structural and functional effect induced by these two RTT-associated mutations. These results represent an example of how a given mutation may show different effects (sometimes opposing effects) depending on the molecular context.
publishDate 2020
dc.date.none.fl_str_mv 2
2020-01-01
2020
2020-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/236604
https://dx.doi.org/urn:doi:10.3390/biom10111533
url https://ddd.uab.cat/record/236604
https://dx.doi.org/urn:doi:10.3390/biom10111533
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 BFU2016-78232-P
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI15-00663
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 PI18-00349
Agencia Estatal de Investigación https://doi.org/10.13039/501100011033 BES-2017-080739
Instituto de Salud Carlos III https://doi.org/10.13039/501100004587 CPII13-00017
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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