Roles of protein-protein interactions in nuclear signal transductions

通过该基金组成员之间的密切合作，在转录、DNA修复和染色质重塑领域有许多新的发现。其中之一是由白川及其同事研究的MBD 1的甲基-CpG结合结构域与甲基化DNA之间的复合物结构。在脊椎动物中，CpG甲基化对于基因活性、基因组稳定性和染色质结构的调节是重要的; DNA甲基化状态的差异与印记现象、发育和致癌相关。甲基化信号由含有甲基-CpG结合结构域（MBD）的蛋白质因子解释。白川和同事已经确定了与甲基化DNA结合的人甲基化依赖性转录调节因子MBD 1的MBD的溶液结构。甲基化位点的甲基通过与MBD家族中完全保守的精氨酸、酪氨酸和丝氨酸残基的脂族和芳族部分的广泛疏水接触而被识别。CG序列的区别是由于相同的精氨酸和酪氨酸残基。该结构表明MBD如何在不遇到核心组蛋白的空间干扰的情况下进入核小体DNA。它还表明，在Rett综合征中突变的MeCP 2的一些残基位于蛋白质-DNA界面，为理解这些突变的后果提供了结构基础。

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.