Tyr120Asp mutation alters domain flexibility and dynamics of MeCP2 DNA binding domain leading to impaired DNA interaction: Atomistic characterization of a Rett syndrome causing mutation

Biochim Biophys Acta Gen Subj. 2018 May;1862(5):1180-1189. doi: 10.1016/j.bbagen.2018.02.005. Epub 2018 Feb 8.

Abstract

Mutations in the X-linked MECP2 gene represent the main origin of Rett syndrome, causing a profound intellectual disability in females. MeCP2 is an epigenetic transcriptional regulator containing two main functional domains: a methyl-CpG binding domain (MBD) and a transcription repression domain (TRD). Over 600 pathogenic mutations were reported to affect the whole protein; almost half of missense mutations affect the MBD. Understanding the impact of these mutations on the MBD structure and interaction with DNA will foster the comprehension of their pathogenicity and possibly genotype/phenotype correlation studies. Herein, we use molecular dynamics simulations to obtain a detailed view of the dynamics of WT and mutated MBD in the presence and absence of DNA. The pathogenic mutation Y120D is used as paradigm for our studies. Further, since the Y120 residue was previously found to be a phosphorylation site, we characterize the dynamic profile of the MBD also in the presence of Y120 phosphorylation (pY120). We found that addition of a phosphate group to Y120 or mutation in aspartic acid affect domain mobility that samples an alternative conformational space with respect to the WT, leading to impaired ability to interact with DNA. Experimental assays showing a significant reduction in the binding affinity between the mutated MBD and the DNA confirmed our predictions.

Keywords: DNA binging domain; Docking; MeCP2 Methyl-CpG-binding protein 2; Molecular dynamics simulation; Rett causing mutation; Rett syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution
  • DNA / chemistry*
  • DNA / genetics
  • DNA / metabolism
  • Female
  • Humans
  • Methyl-CpG-Binding Protein 2 / chemistry*
  • Methyl-CpG-Binding Protein 2 / genetics
  • Methyl-CpG-Binding Protein 2 / metabolism
  • Molecular Dynamics Simulation*
  • Mutation, Missense*
  • Protein Domains
  • Rett Syndrome*

Substances

  • MECP2 protein, human
  • Methyl-CpG-Binding Protein 2
  • DNA