The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site

Methyl-CpG binding protein 2 (MeCP2) preferentially interacts with methylated DNA and it is involved in epigenetic regulation and chromatin remodelling. Mutations in MeCP2 are linked to Rett syndrome, the leading cause of intellectual retardation in girls and causing mental, motor and growth impairm...

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Autores: Clavería Gimeno, Rafael, Lanuza, Pilar M., Morales-Chueca, Ignacio, Jorge-Torres, Olga C., Vega, Sonia, Abian, Olga, Esteller, Manel, 1968-, Velazquez-Campoy, Adrian
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2017
País:España
Recursos:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/120612
Acesso em linha:https://hdl.handle.net/2445/120612
Access Level:acceso abierto
Palavra-chave:ADN
Metilació
Epigenètica
Proteïnes
DNA
Methylation
Epigenetics
Proteins
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spelling The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction siteClavería Gimeno, RafaelLanuza, Pilar M.Morales-Chueca, IgnacioJorge-Torres, Olga C.Vega, SoniaAbian, OlgaEsteller, Manel, 1968-Velazquez-Campoy, AdrianADNMetilacióEpigenèticaProteïnesDNAMethylationEpigeneticsProteinsMethyl-CpG binding protein 2 (MeCP2) preferentially interacts with methylated DNA and it is involved in epigenetic regulation and chromatin remodelling. Mutations in MeCP2 are linked to Rett syndrome, the leading cause of intellectual retardation in girls and causing mental, motor and growth impairment. Unstructured regions in MeCP2 provide the plasticity for establishing interactions with multiple binding partners. We present a biophysical characterization of the methyl binding domain (MBD) from MeCP2 reporting the contribution of flanking domains to its structural stability and dsDNA interaction. The flanking disordered intervening domain (ID) increased the structural stability of MBD, modified its dsDNA binding profile from an entropically-driven moderate-affinity binding to an overwhelmingly enthalpically-driven high-affinity binding. Additionally, ID provided an additional site for simultaneously and autonomously binding an independent dsDNA molecule, which is a key feature linked to the chromatin remodelling and looping activity of MeCP2, as well as its ability to interact with nucleosomes replacing histone H1. The dsDNA interaction is characterized by an unusually large heat capacity linked to a cluster of water molecules trapped within the binding interface. The dynamics of disordered regions together with extrinsic factors are key determinants of MeCP2 global structural properties and functional capabilities.Nature Publishing Group2017info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/120612Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/srep41635Scientific Reports, 2017, vol. 7, p. 41635https://doi.org/10.1038/srep41635cc-by (c) Claveria-Gimeno, Rafael et al., 2017http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1206122026-05-27T06:46:51Z
dc.title.none.fl_str_mv The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site
title The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site
spellingShingle The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site
Clavería Gimeno, Rafael
ADN
Metilació
Epigenètica
Proteïnes
DNA
Methylation
Epigenetics
Proteins
title_short The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site
title_full The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site
title_fullStr The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site
title_full_unstemmed The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site
title_sort The intervening domain from MeCP2 enhances the DNA affinity of the methyl binding domain and provides an independent DNA interaction site
dc.creator.none.fl_str_mv Clavería Gimeno, Rafael
Lanuza, Pilar M.
Morales-Chueca, Ignacio
Jorge-Torres, Olga C.
Vega, Sonia
Abian, Olga
Esteller, Manel, 1968-
Velazquez-Campoy, Adrian
author Clavería Gimeno, Rafael
author_facet Clavería Gimeno, Rafael
Lanuza, Pilar M.
Morales-Chueca, Ignacio
Jorge-Torres, Olga C.
Vega, Sonia
Abian, Olga
Esteller, Manel, 1968-
Velazquez-Campoy, Adrian
author_role author
author2 Lanuza, Pilar M.
Morales-Chueca, Ignacio
Jorge-Torres, Olga C.
Vega, Sonia
Abian, Olga
Esteller, Manel, 1968-
Velazquez-Campoy, Adrian
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ADN
Metilació
Epigenètica
Proteïnes
DNA
Methylation
Epigenetics
Proteins
topic ADN
Metilació
Epigenètica
Proteïnes
DNA
Methylation
Epigenetics
Proteins
description Methyl-CpG binding protein 2 (MeCP2) preferentially interacts with methylated DNA and it is involved in epigenetic regulation and chromatin remodelling. Mutations in MeCP2 are linked to Rett syndrome, the leading cause of intellectual retardation in girls and causing mental, motor and growth impairment. Unstructured regions in MeCP2 provide the plasticity for establishing interactions with multiple binding partners. We present a biophysical characterization of the methyl binding domain (MBD) from MeCP2 reporting the contribution of flanking domains to its structural stability and dsDNA interaction. The flanking disordered intervening domain (ID) increased the structural stability of MBD, modified its dsDNA binding profile from an entropically-driven moderate-affinity binding to an overwhelmingly enthalpically-driven high-affinity binding. Additionally, ID provided an additional site for simultaneously and autonomously binding an independent dsDNA molecule, which is a key feature linked to the chromatin remodelling and looping activity of MeCP2, as well as its ability to interact with nucleosomes replacing histone H1. The dsDNA interaction is characterized by an unusually large heat capacity linked to a cluster of water molecules trapped within the binding interface. The dynamics of disordered regions together with extrinsic factors are key determinants of MeCP2 global structural properties and functional capabilities.
publishDate 2017
dc.date.none.fl_str_mv 2017
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/2445/120612
url https://hdl.handle.net/2445/120612
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/10.1038/srep41635
Scientific Reports, 2017, vol. 7, p. 41635
https://doi.org/10.1038/srep41635
dc.rights.none.fl_str_mv cc-by (c) Claveria-Gimeno, Rafael et al., 2017
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Claveria-Gimeno, Rafael et al., 2017
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 Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
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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score 15,301603

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