Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-binding 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 female...

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Detalles Bibliográficos
Autores: Ortega Alarcón, David, Clavería Gimeno, Rafael, Vega, Sonia, Jorge Torres, Olga C., Esteller, Manel, 1968-, Abian, Olga, Velázquez Campoy, Adrian
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/174889
Acceso en línea:https://hdl.handle.net/2445/174889
Access Level:acceso abierto
Palabra clave:Síndrome de Rett
Proteïnes
Rett syndrome
Proteins
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spelling Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2Ortega Alarcón, DavidClavería Gimeno, RafaelVega, SoniaJorge Torres, Olga C.Esteller, Manel, 1968-Abian, OlgaVelázquez Campoy, AdrianSíndrome de RettProteïnesRett syndromeProteinsMethyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-binding 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 (N-terminal 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.MDPI2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/174889Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/biom10111533Biomolecules, 2020, vol. 10, num. 11https://doi.org/10.3390/biom10111533cc-by (c) Ortega Alarcón, David et al., 2020http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1748892026-05-27T06:46:51Z
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 Alarcón, David
Síndrome de Rett
Proteïnes
Rett syndrome
Proteins
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 Alarcón, David
Clavería Gimeno, Rafael
Vega, Sonia
Jorge Torres, Olga C.
Esteller, Manel, 1968-
Abian, Olga
Velázquez Campoy, Adrian
author Ortega Alarcón, David
author_facet Ortega Alarcón, David
Clavería Gimeno, Rafael
Vega, Sonia
Jorge Torres, Olga C.
Esteller, Manel, 1968-
Abian, Olga
Velázquez Campoy, Adrian
author_role author
author2 Clavería Gimeno, Rafael
Vega, Sonia
Jorge Torres, Olga C.
Esteller, Manel, 1968-
Abian, Olga
Velázquez Campoy, Adrian
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Síndrome de Rett
Proteïnes
Rett syndrome
Proteins
topic Síndrome de Rett
Proteïnes
Rett syndrome
Proteins
description Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-binding 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 (N-terminal 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 2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/174889
url https://hdl.handle.net/2445/174889
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/biom10111533
Biomolecules, 2020, vol. 10, num. 11
https://doi.org/10.3390/biom10111533
dc.rights.none.fl_str_mv cc-by (c) Ortega Alarcón, David et al., 2020
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Ortega Alarcón, David et al., 2020
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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