Home > Articles > Published articles > Molecular context-dependent effects induced by rett syndrome-associated mutations in mecp2 |
Date: | 2020 |
Abstract: | 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. |
Grants: | Ministerio de Economía y Competitividad BFU2016-78232-P Instituto de Salud Carlos III PI15-00663 Instituto de Salud Carlos III PI18-00349 Ministerio de Ciencia e Innovación BES-2017-080739 Instituto de Salud Carlos III CPII13-00017 |
Note: | Altres ajuts: This research was funded by the Diputación General de Aragón (Protein Targets and Bioactive Compounds Group E45_17R to A.V.C. and Digestive Pathology Group B25_17R to O.A.); and the Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (CIBERehd). |
Rights: | Aquest 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. |
Language: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Subject: | Methyl-CpG-binding protein 2 (MeCP2) ; Rett syndrome ; Intrinsically disordered protein (IDP) ; Isothermal titration calorimetry (ITC) ; Protein stability ; Protein-DNA interaction |
Published in: | Biomolecules, Vol. 10 Núm. 11 (november 2020) , p. 1-18, ISSN 2218-273X |
19 p, 3.1 MB |