UHRF1 discriminates against binding to fully-methylated CpG-Sites by steric repulsion
| Autor: | Ronen Zangi, Caterina Bianca Neve Aurora Bianchi |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
HMG-box
Base pair Ubiquitin-Protein Ligases Biophysics Molecular Dynamics Simulation 01 natural sciences Biochemistry 03 medical and health sciences 0103 physical sciences Humans Protein–DNA interaction 030304 developmental biology chemistry.chemical_classification 0303 health sciences DNA ligase 010304 chemical physics Chemistry Organic Chemistry DNA DNA-binding domain DNA Methylation Protein Structure Tertiary DNA binding site CCAAT-Enhancer-Binding Proteins Thermodynamics DNA supercoil CpG Islands Binding domain |
| Zdroj: | Biophysical Chemistry. 171:38-45 |
| ISSN: | 0301-4622 |
| Popis: | Cytosine methylation of CpG dinucleotide sequence is an epigenetic mark on the DNA that regulates gene expression, chromatin structure, and genome stability. Although the enzyme that catalyzes the methylation reaction after replication is Dnmt1, it was found that the protein UHRF1 is essential for maintaining DNA methylation. UHRF1 exhibits preferential binding to hemi-methylated DNA relative to both unmethylated and fully-methylated DNA strands. In this paper we report results from molecular dynamics simulations aiming to elucidate the mechanism for the discrimination of UHRF1 to bind fully-methylated DNA. From alchemical mutation free energy calculations we find that the binding affinity of fully-methylated DNA to UHRF1 is weaker by 17.9 kJ/mol relative to the binding of hemi-methylated DNA. Structural analyses reveal, in agreement with the steric clash model, that a methyl group at the C5 position of the target cytosine induces a displacement of the NKR finger domain away from the DNA. As a result a net loss of, approximately, one hydrogen bond between the protein and the DNA is observed. These weakened protein–DNA interactions are located between the target cytosine and the NKR domain, as well as, between the flipped methylcytosine and the binding pocket of the SRA domain. Due to the conformational changes of the fully-methylated bound complex, water molecules intrude the protein–DNA interface and substitute the majority of the hydrogen bonds that are lost. |
| Databáze: | OpenAIRE |
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