Influence of the disordered domain structure of MeCP2 on its structural stability and dsDNA interaction

David Ortega-Alarcon,Rafael Claveria-Gimeno,Sonia Vega,Olga C Jorge-Torres,Manel Esteller,Olga Abian,Adrian Velazquez-Campoy

doi:10.1016/j.ijbiomac.2021.01.206

Abstract

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-associated structural protein. MeCP2 deregulation results in two neurodevelopmental disorders: MeCP2 dysfunction is associated with Rett syndrome, while excess of activity is associated with MeCP2 duplication syndrome. MeCP2 is an intrinsically disordered protein (IDP) constituted by six structural domains with variable, small percentage of well-defined secondary structure. Two domains, methyl-CpG binding domain (MBD) and transcription repressor domain (TRD), are the elements responsible for dsDNA binding ability and recruitment of the gene transcription/silencing machinery, respectively. Previously we studied the influence of the completely disordered, MBD-flanking domains (N-terminal domain, NTD, and intervening domain, ID) on the structural and functional features of the MBD (Claveria-Gimeno, R. et al. Sci Rep. 2017, 7, 41,635). Here we report the biophysical study of the influence of the remaining domains (transcriptional repressor domain, TRD, and C-terminal domains, CTDα and CTDβ) on the structural stability of MBD and the dsDNA binding capabilities of MBD and ID. The influence of distant disordered domains on MBD properties makes it necessary to consider the NTD-MBD-ID variant as the minimal protein construct for studying dsDNA/chromatin binding properties, while the full-length protein should be considered for transcriptional regulation studies.

Highlights

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator involved in early stages of neuronal development, differentiation, maturation, and synaptic plasticity control [1]
In the case of MeCP2, we have recently provided evidence for that phenomenon: 1) N-terminal domain (NTD) and intervening domain (ID), two completely disordered domains flanking the methyl-CpG binding domain (MBD), increase significantly the thermal stability of the MBD [29]; and 2) the two MeCP2 isoforms E1 and E2, which only differ in a few N-terminal aminoacids in the completely disordered domain NTD, show different thermal stability [28]
MeCP2 is a potential pharmacological protein target associated with RTT and MeCP2 duplication syndrome (MDS), two neurological disorders with similar phenotypic features

Summary

Introduction

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator involved in early stages of neuronal development, differentiation, maturation, and synaptic plasticity control [1]. Besides this promoterspecific dsDNA interaction required for finely tuning gene transcription, MeCP2 binds massively to chromatin, acting as a chromatin. ⁎ Correspondence to: Olga Abian, Instituto Aragonés de Ciencias de la Salud (IACS), San Juan Bosco 13, 50009 Zaragoza, Spain. ⁎⁎ Correspondence to: Adrián Velázquez-Campoy, Institute BIFI - University of Zaragoza, Mariano Esquillor s/n, 50018 Zaragoza, Spain.

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