Roles of protein-protein interactions in nuclear signal transductions

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Through close collaborations between members of this grant group, many new findings in the field of transcription, DNA repair and chromatin remodeling were reported. One of them is the structure of the complex between the methyl-CpG-binding domain of MBD1 and a methylated DNA, by Shirakawa and co-workers. CpG methylation in vertebrates is important for the regulation of gene activity, genomic stability and chromatin structure ; differences in the DNA-methylation status are associated with imprinting phenomena, development, and carcinogenesis. Methylation signals are interpreted by protein factors that contain methyl-CpG-binding domains (MBDs). Shirakawa and co-wokers have determined solution structure of the MBD of the human methylation-dependent transcriptional regulator MBD1 bound to a methylated DNA. The methyl groups at the methylation site are recognized through extensive hydrophobic contacts with aliphatic and aromatic portions of arginine, tyrosine, and serine residues that are totally conserved among the MBD family. Discrimination of the CG sequence is due to the sama arginine and tyrosine residues. The structure indicates how MBD may access to nucleosomal DNA without encountering steric interference from core histones. It also suggests that some residues of MeCP2 that are mutated in Rett syndrome are located at the protein-DNA interface, providing a structural basis to understand the consequence of these mutations.