MeCP2 binding to DNA depends upon hydration at methyl-CpG

Area of Science:

• Molecular Biology
• Epigenetics
• Structural Biology

Background:

• Methyl-CpG-binding protein 2 (MeCP2) is crucial for gene silencing via methylated DNA.
• Current models propose hydrophobic interactions mediate MeCP2 binding specificity.

Purpose of the Study:

• To elucidate the precise molecular interactions governing MeCP2 binding to methylated DNA.
• To investigate the structural basis of MeCP2's recognition of methylated CpG sites.

Main Methods:

• X-ray crystallography of a methylated DNA-MeCP2 methyl-CpG-binding domain (MBD) cocrystal.

Main Results:

• MeCP2's methyl groups interact with a hydrophilic surface and water molecules, not a hydrophobic patch.
• The binding mechanism involves recognition of DNA groove hydration rather than solely cytosine methylation.
• A specific residue (T158) involved in Rett syndrome mutations plays a unique structural role.

Conclusions:

• MeCP2 binding specificity is mediated by recognizing the hydration of methylated DNA's major groove.
• This revised understanding offers insights into MeCP2's role in gene regulation and Rett syndrome pathogenesis.