MBD4 has two primary binding domains, its methyl-CpG binding domain (MBD) and its thymine glycosylase domain (TGD) which are separated by ~300 amino acids. MBD4’s MBD domain is a reader domain which preferentially recognises and binds in the major groove of methyl-CpG sites. Unlike other proteins of the MBD family, MBD4 has a slightly varied but unique structure allowing it to recognise mismatches at these DNA sites, occurring primarily from spontaneous deamination of 5-methylcytosine to thymine. On the other hand, the TGD domain is docked to the DNA via the minor groove in which it can then excise thymine if bound to a mismatched 5mCG/TG site. Following excision of a base by its TGD domain, MBD4 detaches and allows other enzymes to work together to repair the excised base. This is an integral function in maintaining genomic stability as otherwise if left unaltered will cause transition mutations.
All information regarding the complex’s structure was taken from the single research paper in the references.
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