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...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-11-01
|
| Series: | Biomolecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2218-273X/10/11/1533 |
| _version_ | 1827702450012815360 |
|---|---|
| author | David Ortega-Alarcon Rafael Claveria-Gimeno Sonia Vega Olga C. Jorge-Torres Manel Esteller Olga Abian Adrian Velazquez-Campoy |
| author_facet | David Ortega-Alarcon Rafael Claveria-Gimeno Sonia Vega Olga C. Jorge-Torres Manel Esteller Olga Abian Adrian Velazquez-Campoy |
| author_sort | David Ortega-Alarcon |
| collection | DOAJ |
| 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. <b>2017</b>, <i>7</i>, 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. |
| first_indexed | 2024-03-10T14:57:30Z |
| format | Article |
| id | doaj.art-0a95739694494719b4ff128e916fc048 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T14:57:30Z |
| publishDate | 2020-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-0a95739694494719b4ff128e916fc0482023-11-20T20:28:28ZengMDPI AGBiomolecules2218-273X2020-11-011011153310.3390/biom10111533Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2David Ortega-Alarcon0Rafael Claveria-Gimeno1Sonia Vega2Olga C. Jorge-Torres3Manel Esteller4Olga Abian5Adrian Velazquez-Campoy6Institute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, SpainInstitute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, SpainInstitute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, SpainJosep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, SpainJosep Carreras Leukaemia Research Institute (IJC), 08916 Badalona, SpainInstitute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, SpainInstitute of Biocomputation and Physics of Complex Systems (BIFI), Joint Units IQFR-CSIC-BIFI, and GBsC-CSIC-BIFI, Universidad de Zaragoza, 50018 Zaragoza, SpainMethyl-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. <b>2017</b>, <i>7</i>, 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.https://www.mdpi.com/2218-273X/10/11/1533Methyl-CpG-binding protein 2 (MeCP2)Rett syndromeintrinsically disordered protein (IDP)protein stabilityprotein-DNA interactionisothermal titration calorimetry (ITC) |
| spellingShingle | David Ortega-Alarcon Rafael Claveria-Gimeno Sonia Vega Olga C. Jorge-Torres Manel Esteller Olga Abian Adrian Velazquez-Campoy Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2 Biomolecules Methyl-CpG-binding protein 2 (MeCP2) Rett syndrome intrinsically disordered protein (IDP) protein stability protein-DNA interaction isothermal titration calorimetry (ITC) |
| 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 | Methyl-CpG-binding protein 2 (MeCP2) Rett syndrome intrinsically disordered protein (IDP) protein stability protein-DNA interaction isothermal titration calorimetry (ITC) |
| url | https://www.mdpi.com/2218-273X/10/11/1533 |
| work_keys_str_mv | AT davidortegaalarcon molecularcontextdependenteffectsinducedbyrettsyndromeassociatedmutationsinmecp2 AT rafaelclaveriagimeno molecularcontextdependenteffectsinducedbyrettsyndromeassociatedmutationsinmecp2 AT soniavega molecularcontextdependenteffectsinducedbyrettsyndromeassociatedmutationsinmecp2 AT olgacjorgetorres molecularcontextdependenteffectsinducedbyrettsyndromeassociatedmutationsinmecp2 AT manelesteller molecularcontextdependenteffectsinducedbyrettsyndromeassociatedmutationsinmecp2 AT olgaabian molecularcontextdependenteffectsinducedbyrettsyndromeassociatedmutationsinmecp2 AT adrianvelazquezcampoy molecularcontextdependenteffectsinducedbyrettsyndromeassociatedmutationsinmecp2 |