Structural insights into a dual-specificity histone demethylase ceKDM7A from Caenorhabditis elegans  

作　　者：Ying Yang Lulu Hu Ping Wang Haifeng Hou Yan Lin Yi Liu Ze Li Rui Gong Xiang Feng Lu Zhou Wen Zhang Yuhui Dong Huirong Yang Hanqing Lin Yiqin Wang Charlie Degui Chen Yanhui Xu 

机构地区：[1]Cancer Institute, Shanghai Cancer Center, Fudan University Department of Ontology, Shanghai Medical College, Fudan University, shanghai 200032, China [2]School of Life Sciences, Fudan University, 220 Han-Dan Road, Shanghai 200433, China [3]Institutes of Biomedical Sciences, Fudan University, 130 Dong-An Road, Shanghai 200032, China [4]Beijing Synchrotron Radiation Facility, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China [5]School of Pharmacy, Fudan University, South Chemistry Building, Room 315, 826 Zhangheng Road, Shanghai 201203, China [6]State Key Laboratory of Molecular Biology, Shanghai Key laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China

出　　处：《Cell Research》2010年第8期886-898,共13页细胞研究（英文版）

摘　　要：Histone lysine methylation can be removed by JmjC domain-containing proteins in a sequence- and methylationstate-specific manner. However, how substrate specificity is determined and how the enzymes are regulated were largely unknown. We recently found that ceKDM7A, a PHD- and JmjC domain-containing protein, is a histone demethylase specific for H3K9me2 and H3K27me2, and the PHD finger binding to H3K4me3 guides the demethylation activity in vivo. To provide structural insight into the molecular mechanisms for the enzymatic activity and the function of the PHD finger, we solved six crystal structures of the enzyme in apo form and in complex with single or two peptides containing various combinations of H3K4me3, H3K9me2, and H3K27me2 modifications. The structures indicate that H3Kgme2 and H3K27me2 interact with ceKDMTA in a similar fashion, and that the peptide-binding specificity is determined by a network of specific interactions. The geometrical measurement of the structures also revealed that H3K4me3 associated with the PHD finger and H3K9me2 bound to the JmjC domain are from two separate molecules, suggesting a trans-histone peptide-binding mechanism. Thus, our systemic structural studies reveal not only the substrate recognition by the catalytic domain but also more importantly, the molecular mechanism of dual specifieity of ceDKM7A for both H3K9me2 and H3K27me2.

关 键 词：HISTONE methylation DEMETHYLASE structure PHD JMJC 

分 类 号：Q343.2[生物学—遗传学] TS202.3[轻工技术与工程—食品科学]