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

Claveria-Gimeno, R. ; Lanuza, P.M. (Universidad de Zaragoza) ; Morales-Chueca, I. ; Jorge-Torres, O.C. ; Vega, S. ; Abian, O. (Universidad de Zaragoza) ; Esteller, M. ; Velazquez-Campoy, A. (Universidad de Zaragoza)

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/srep41635

Año: 2017

Publicado en: Scientific reports 7 (2017), 41635
ISSN: 2045-2322

Factor impacto JCR: 4.122 (2017)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 12 / 64 = 0.188 (2017) - Q1 - T1

Factor impacto SCIMAGO: 1.533 - Multidisciplinary (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/B01
Financiación: info:eu-repo/grantAgreement/ES/DGA/B136-13
Financiación: info:eu-repo/grantAgreement/ES/DGA/B89
Financiación: info:eu-repo/grantAgreement/ES/FIS/PI15-00663
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CPII13-0017
Financiación: info:eu-repo/grantAgreement/ES/MEC/FPU13-3870
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2013-47064-P
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)