Methyl binding domains

Changes in chromatin structure (and resulting changes in transcriptional activity) as a result of histone modifications are thought to occur in one of two ways modifications may result in steric or electrostatic changes to histone tails which change the nature of the histones interactions with DNA, or, alternatively, modifications may recruit modification-specific binding domains 

1 Histone-modifying Enzymes are Targeted by Methyl Binding Domains 

The contributions of MBDs to disease have been reeently reviewed, suggesting that some MBDs may present therapeutic targets. Several examples are 

Binding domain subfamily Protein Cognate sequence Disease associations 

MBT L3MBT1L HlbK26me2/mel H4K20me2/mel Malignant brain tumour formation in Drosophila 

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Fig. 8. Proposed models that link histone methylation to DNA methylation (for details see Section 5.2). Methylated cytosines attract histone methyltransferases that contain a methyl-binding domain or a methyl-CpG binding protein (MeCP2) that recruits histone methylase activities these introduce methyl groups into the histone tails. The binding of chromodomain HPl proteins to H3 tails methylated at lysine 9 generates a secondary layer of repressive chromatin structure, (b) In a reverse scenario, methylated histone tails attract chromodomain-binding proteins, which in turn recruit Dmnts to methylate adjacent DNA sequences.

Table 5.6 Selected human methyl binding domains (MBDs).

In addition protein domains have been identified which bind to modified histone tails. The so-called bromodomains bind to acetylated histone tail, but have little or no affinity to unmodified tails. Further known binding domains include chromodomains and SANT domains which possess preferential binding to methylated and unmodified tails. 

The conformation and orientation of adsorbed proteins has been examined with monoclonal antibodies that recognize a specific site in a protein of interest. Keselowsky et al. examined the conformation of Fn adsorbed to SAMs that carried methyl, hydroxyl, carboxyl, and amine groups [79]. They used monoclonal antibodies that recognized the central cell-binding domain of Fn near the RGD motif. Different SAM functionalities differentially modulated the binding affinities of the monoclonal antibodies (OH > COOH = NH2 > CH3). The strength of cell adhesion to these... 

HAMP HAMP (Histidine kinases, Adenylyl cyclases, Methyl binding proteins, Phosphatases) domain E(MF)AB 0(0) 0(0) ... 

BRCT BRCAl C-terminus-like DBD DNA-binding domain dPARP Drosophila PARP MPTP l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine NAD+ Nicotinamide adenine dinucleotide NAm Nicotinamide NLS Nuclear locahzation signal OAADPR O-acetyl-ADP-ribose PAR Poly(ADP-ribose) PARG Poly(ADP-ribose) glycohydrolase PARP Poly(ADP-ribose) polymerase PARylation poly(ADP-ribosyl)ation... 

Zeng L, Zhou MM (2002) Bromodomain an acetyl-lysine binding domain. EEBS letters 513 124-128 Zhang Y, Reinberg D (2001) Transcription regulation by histone methylation interplay between different covalent modifications of the core histone tails. Genes Dev 15 2343-2360... 

Although chemically modifying DNA have distinctive implications for chromatin transitions and fiber structure in the presence of HI [250], in vivo these effects appear to work in concert with chromosomal proteins. 5 -Methylcytosines are specifically bound by members of the MBD (methyl-CpG-binding-domain) family, such as MeCP2 (Methyl-Cytosine binding Protein 2) and MBDl. These proteins have been shown to interact with HDACs and provide a casual link between DNA methylation, histone deacetylation and transcriptional repression [251-253]. 

The solution structure of the methyl-CpG binding domain of human MBDl complexed with a methylated oligonucleotide has been recently presented [164], The structure indicates how MBD may access nucleosomal DNA without encountering steric hindrance from the histone octamer. 

The past few years witnessed some important developments that established a molecular link between CpG methylation and the status of histone acetylation. It was shown that the methyl-binding protein MeCp2 contains a transcriptional repressor domain that interacts directly with the multiprotein corepressor complex mSin3A [84,86]. Antibodies against MeCP2 coprecipitated mSin3A, HDACl and HDAC2, and the deacetylase inhibitor trichostatin A (TSA) relieved the repression. 

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