Methyl-CpG-binding domain protein 3 (MBD3) is a transcriptional repressor and plays a role in gene silencing. It binds to DNA with a preference for sites containing methylated CpG dinucleotides but only as part of a complex [, ]. It forms a heterodimer with MBD2 []and is a component of the NuRD []and the MeCP1 []complexes.
CpG-methylation is a frequently occurring epigenetic modification of vertebrate genomes resulting in transcriptional repression. This domain is found at the C terminus of the methyl-CpG-binding domain (MBD) containing proteins MBD2 []and MBD3 []. The latter was shown to not bind directly to methyl-CpG DNA but rather interact with components of the NuRD/Mi2 complex [], an abundant deacetylase complex.
Methylation at CpG dinucleotide, the most common DNA modification ineukaryotes, has been correlated with gene silencing associated with variousphenomena such as genomic imprinting, transposon and chromosome X inactivation, differentiation, and cancer. Effects of DNA methylation are mediated through proteins which bind to symmetrically methylated CpGs. Such proteins contain a specific domain of ~70 residues, the methyl-CpG-binding domain (MBD), which is linked to additional domains associated with chromatin, such as the bromodomain, the AT hook motif,the SET domain, or the PHD finger. MBD-containing proteins appear to act as structural proteins, which recruit a variety of histone deacetylase (HDAC) complexes and chromatin remodelling factors, leading to chromatin compaction and, consequently, to transcriptional repression. The MBD of MeCP2, MBD1, MBD2, MBD4 and BAZ2 mediates binding to DNA, in case of MeCP2, MBD1 and MBD2 preferentially to methylated CpG. In case of human MBD3 and SETDB1 the MBD has been shown to mediate protein-protein interactions [, ].The MBD folds into an alpha/beta sandwich structure comprising a layer oftwisted beta sheet, backed by another layer formed by the alpha1 helix and ahairpin loop at the C terminus. These layers are both amphipathic, with the alpha1 helix and the beta sheet lying parallel and the hydrophobic faces tightly packed against each other. The beta sheet is composed of two long inner strands (beta2 and beta3) sandwiched by two shorter outer strands (beta1 and beta4) [].
