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Cited by 18Genetics and Neurodevelopmental DisordersProtein Structure and DynamicsGenomics and Rare Diseases

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

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D'Annessa, Ilda, Gandaglia, Anna, Brivio, Elena, Stefanelli, Gilda, Frasca, Angelisa, Landsberger, Nicoletta, Di Marino, Daniele·2018·Biochimica et Biophysica Acta (BBA) - General Subjects
DOI 10.1016/j.bbagen.2018.02.005
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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.

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  • Nsdhl protein levels are reduced by approximately 50% in the brain of KI Mecp2 Y120D/y mouse model.

    “Importantly, Nsdhl protein levels were similarly reduced by approximately 50% in the brain of the KI Mecp2 Y120D/y mouse model, which carries a phospho-mimetic missense mutation and phenotypically recapitulates the null mouse (Supplementary Figure 6A) (D'Annessa et al., 2018;Gandaglia et al., 2019).”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as D'Annessa et al., 2018

    Section 3.3 (pp. 9–10) tests DNA binding by MeCP2 Y120D protein fragments, not Nsdhl levels in mouse brain. Searches for Nsdhl and the Y120D knock-in mouse model found no passage reporting an approximately 50% reduction. (LLM, conf=0.78)

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  15. [45]45. Ghosh, R.P., Horowitz-Scherer, R.A., Nikitina, T., Gierasch, L.M. and Woodcock, C.L. (2008) Rett syndromecausing mutations in human MeCP2 result in diverse structural changes that impact folding and DNA interactions. Journal of Biological Chemistry , 283 , 20523-20534. <!-- image --> <!-- image --> <!-- image --> B <!-- image --> <!-- image --> <!-- image --> Supplementary Table T1. Hydrogen Bonds present in the MeCP2 MBD-DNA X-Ray structure and in the MD trajectory in the last 230 ns of simulation. The interactions present only in the X-ray or in the trajectory are highlighted in bold. Figure S1. (A) Per-residue RMSF of the MeCP2 MBD domain in complex with DNA. The loop L1, important for the interaction with the nucleic acid, is highlighted. (B) RMSD of the C α atoms. The grey box underlines the equilibration time after which the protein reaches a plateau. <!-- image --> Figure S2. (A) RMSD of the C α atoms for the WT (black line), pY120 (red line) and Y120D (green line) domains. The grey box underlines the equilibration time avoided to carry out further analyses. (B) Per-residue RMSF of the WT (black line), pY120 (red line) and Y120D (green line) domains. The loop L1, important for the interaction with the nucleic acid, is highlighted. <!-- image --> Figure S3. Cumulative percentage of the description of the motion by the first 40 eigenvectors in the three systems: WT=black dots, pY120=red dots, Y120D=green dots. <!-- image --> Figure S4. Numbers of structures represented in each cluster. WT=black bar, pY120=red bar, Y120D=green bar. <!-- image --> Figure S5. Upper view of the superposition on the DNA atoms between the MeCP2 MBD-DNA Xray structure and all the best pose of each family of docked structures obtained for pY120 (A) and Y120D (B). The domain from the X-ray complex is depicted in grey in both panels. For the sake of clearness only the DNA from the X-ray is shown. <!-- image -->

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Authors
D'Annessa, I., Gandaglia, A., Brivio, E., Stefanelli, G., Frasca, A., Landsberger, N., & Di Marino, D.
Affiliations
  • IRCCS Ospedale San Raffaele (IT)
  • University of Milan (IT)
Corresponding author
Landsberger, Nicoletta
ORCID
Venue
Biochimica et Biophysica Acta (BBA) - General Subjects
Publisher
Elsevier BV
Published
2018-05
Volume
1862
Issue
5
Pages
1180-1189
ISSN
0304-4165 (ISSN-L)
DOI
10.1016/j.bbagen.2018.02.005
OpenAlex
W2794431074
Cited by
18
References
1
Citations by year
2026: 2 · 2025: 3 · 2022: 1 · 2021: 2 · 2020: 6 · 2019: 3 · 2018: 1
FWCI
1.81
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - General Subjects (publishedVersion)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion)
Funders
  • PERTNET
  • Ministero degli Affari Esteri e della Cooperazione Internazionale
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
MeCP2, Rett syndrome, methyl-CpG binding domain, DNA binding, protein-DNA interactions, domain flexibility, protein dynamics, phosphorylation, genotype-phenotype correlation, missense mutations
MeSH terms
Protein Domains, DNA, Female, Humans, Rett Syndrome, Amino Acid Substitution, Mutation, Missense, Methyl-CpG-Binding Protein 2, Molecular Dynamics Simulation

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