PROSITE documentation PDOC50982

Methyl-CpG-binding domain (MBD) profile

Methylation at CpG dinucleotide, the most common DNA modification in eukaryotes, has been correlated with gene silencing associated with various phenomena such as genomic imprinting, transposon and chromosome X inactivation, differenciation, 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 (see <PDOC00550>), the AT hook motif,the SET domain (see <PDOC50280>), or the PHD finger (see <PDOC50016>). MBD-containing proteins appear to act as structural proteins, which recruit a variety of histone deacetylase (HDAC) complexes and chromatin remodeling 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 [1,2].

The MBD folds into an α/β sandwich structure comprising a layer of twisted β sheet, backed by another layer formed by the α1 helix and a hairpin loop at the C terminus (see <PDB:1IG4>). These layers are both amphipathic, with the α1 helix and the β sheet lying parallel and the hydrophobic faces tighly packed against each other. The β sheet is composed of two long inner strands (β2 and β3) sandwiched by two shorter outer strands (β1 and β4) [3].

Some protein known to contain a MBD domain are listed below:

• Vertebrate methyl-CpG binding proteins MBD1, a transcriptional regulator.
• Vertebrate methyl-CpG binding proteins MBD2.
• Vertebrate methyl-CpG-binding protein 2 (MeCP-2 protein). It is implicated in a human neurological disorder called Rett syndrome. Symptoms of this syndrome are mental retardation, loss of speech and purposeful hand use, autism, ataxia, and stereotypic hand movements.
• Vertebrate bromodomain adjacent to zinc finger domain 2A (BAZ2A/TIP5). It is part of the NoRC, nucleolar remodeling complex, which represses rDNA transcription by recruiting histone methyltransferases, HDACs and DNA methyltransferases.
• Vertebrate bromodomain adjacent to zinc finger domain 2B (BAZ2B).
• Vertebrate histone-lysine N-methyltransferase, H3 lysine-9 specific 4 (EC 2.1.1.43) (SETDB1).
• Vertebrate probable histone-lysine N-methyltransferase, H3 lysine-9 specific (EC 2.1.1.43) (SETDB2 or CLLD8).
• Arabidopsis thaliana AtMBD 1-12. No sequence homology is found between AtMBDs and mammalian MBDs outside the MBD motif.

The profile we developed covers the entire MBD domain.