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Title: Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2
Author: Ortega Alarcón, David
Clavería Gimeno, Rafael
Vega, Sonia
Jorge Torres, Olga C.
Esteller, Manel
Abian, Olga
Velázquez Campoy, Adrian
Keywords: Síndrome de Rett
Rett syndrome
Issue Date: 10-Nov-2020
Publisher: MDPI
Abstract: 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.
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It is part of: Biomolecules, 2020, vol. 10, num. 11
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ISSN: 2218-273X
Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)

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