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...
| Authors: | ; ; ; ; ; ; |
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| Format: | Article |
| Status: | Published version |
| Publication date: | 2020 |
| Country: | España |
| Institution: | Universidad de Barcelona |
| Repository: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/174889 |
| Online Access: | https://hdl.handle.net/2445/174889 |
| Access Level: | Open access |
| Keyword: | Síndrome de Rett Proteïnes Rett syndrome Proteins |
| _version_ | 1878739058543296512 |
|---|---|
| author | Ortega Alarcón, David |
| 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 |
| author_browse | Abian, Olga Clavería Gimeno, Rafael Esteller, Manel, 1968- Jorge Torres, Olga C. Ortega Alarcón, David Vega, Sonia Velázquez Campoy, Adrian |
| 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 |
| collection | Dipòsit Digital de la UB |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_ba490be8f2ffa234fdd866dbcee29b2f |
| institution | Universidad de Barcelona |
| instname_str | Universidad de Barcelona |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:diposit.ub.edu:2445/174889 |
| publishDate | 2020 |
| publishDateSort | 2020 |
| publisher | MDPI |
| publisherStr | MDPI |
| reponame_str | Dipòsit Digital de la UB |
| spelling | Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2 Ortega Alarcón, David Clavería Gimeno, Rafael Vega, Sonia Jorge Torres, Olga C. Esteller, Manel, 1968- Abian, Olga Velázquez Campoy, Adrian Síndrome de Rett Proteïnes Rett syndrome Proteins 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. MDPI https://hdl.handle.net/2445/174889 |
| spellingShingle | Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2 Ortega Alarcón, David Síndrome de Rett Proteïnes Rett syndrome Proteins |
| status_str | publishedVersion |
| title | 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_short | 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 |
| topic | Síndrome de Rett Proteïnes Rett syndrome Proteins |
| topic_facet | Síndrome de Rett Proteïnes Rett syndrome Proteins |
| url | https://hdl.handle.net/2445/174889 |