Roles of protein-protein interactions in nuclear signal transductions

蛋白质-蛋白质相互作用在核信号转导中的作用

基本信息

批准号：
10179102
负责人：
SHIRAKAWA Masahiro
金额：
$ 72.45万
依托单位：
Yokohama City University (2001)Nara Institute of Science and Technology (1998-2000)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas (A)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2001
项目状态：
已结题

项目摘要

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.

通过该资助小组成员之间的密切合作，报告了转录、DNA 修复和染色质重塑领域的许多新发现。其中之一是由 Shirakawa 及其同事研究的 MBD1 的甲基 CpG 结合域和甲基化 DNA 之间的复合物结构。脊椎动物中的 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非常重要； DNA 甲基化状态的差异与印记现象、发育和癌变有关。甲基化信号由包含甲基 CpG 结合域 (MBD) 的蛋白质因子解释。 Shirakawa 及其同事确定了与甲基化 DNA 结合的人类甲基化依赖性转录调节因子 MBD1 的 MBD 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肪族和芳香族部分的广泛疏水接触来识别。 CG 序列的区分是由于 sama 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空间干扰的情况下接触核小体 DNA。它还表明，Rett 综合征中突变的 MeCP2 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。