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

I D'Annessa, A Gandaglia, E Brivio, Gilda Stefanelli, Angelisa Frasca, N Landsberger, Daniele Di Marino

Research output: Contribution to journalArticle

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. © 2018 Elsevier B.V.
Original languageEnglish
Pages (from-to)1180-1189
Number of pages10
JournalBiochimica et Biophysica Acta - General Subjects
Volume1862
Issue number5
DOIs
Publication statusPublished - 2018

Fingerprint

Rett Syndrome
Mutation
Phosphorylation
DNA
Transcription
Aspartic Acid
Molecular dynamics
Assays
X-Linked Genes
Aptitude
Genes
Phosphates
Genetic Association Studies
Missense Mutation
Molecular Dynamics Simulation
Epigenomics
Intellectual Disability
Virulence
Methyl CpG Binding Domain
Computer simulation

Cite this

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. / D'Annessa, I; Gandaglia, A; Brivio, E; Stefanelli, Gilda; Frasca, Angelisa; Landsberger, N; Di Marino, Daniele.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1862, No. 5, 2018, p. 1180-1189.

Research output: Contribution to journalArticle

D'Annessa, I ; Gandaglia, A ; Brivio, E ; Stefanelli, Gilda ; Frasca, Angelisa ; Landsberger, N ; Di Marino, Daniele. / 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. In: Biochimica et Biophysica Acta - General Subjects. 2018 ; Vol. 1862, No. 5. pp. 1180-1189.
@article{e640ed86c13c42eabe9f3572e5568cb2,
title = "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",
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. {\circledC} 2018 Elsevier B.V.",
author = "I D'Annessa and A Gandaglia and E Brivio and Gilda Stefanelli and Angelisa Frasca and N Landsberger and {Di Marino}, Daniele",
year = "2018",
doi = "10.1016/j.bbagen.2018.02.005",
language = "English",
volume = "1862",
pages = "1180--1189",
journal = "Biochimica et Biophysica Acta - General Subjects",
issn = "0304-4165",
publisher = "Elsevier",
number = "5",

}

TY - JOUR

T1 - 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

AU - D'Annessa, I

AU - Gandaglia, A

AU - Brivio, E

AU - Stefanelli, Gilda

AU - Frasca, Angelisa

AU - Landsberger, N

AU - Di Marino, Daniele

PY - 2018

Y1 - 2018

N2 - 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. © 2018 Elsevier B.V.

AB - 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. © 2018 Elsevier B.V.

U2 - 10.1016/j.bbagen.2018.02.005

DO - 10.1016/j.bbagen.2018.02.005

M3 - Article

VL - 1862

SP - 1180

EP - 1189

JO - Biochimica et Biophysica Acta - General Subjects

JF - Biochimica et Biophysica Acta - General Subjects

SN - 0304-4165

IS - 5

ER -