Structural and Evolutionary Basis for the Dual Substrate Selectivity of Human KDM4 Histone Demethylase Family

被引:138
作者
Hillringhaus, Lars [1 ,2 ]
Yue, Wyatt W. [3 ]
Rose, Nathan R. [1 ,2 ]
Ng, Stanley S. [3 ]
Gileadi, Carina [3 ]
Loenarz, Christoph [1 ,2 ]
Bello, Simon H. [1 ,2 ]
Bray, James E. [3 ]
Schofield, Christopher J. [1 ,2 ]
Oppermann, Udo [3 ,4 ]
机构
[1] Univ Oxford, Dept Chem, Oxford OX1 3TA, England
[2] Univ Oxford, Oxford Ctr Integrat Syst Biol, Chem Res Lab, Oxford OX1 3TA, England
[3] Univ Oxford, Struct Genom Consortium, Headington OX3 7DQ, England
[4] Botnar Res Ctr, Natl Inst Hlth Res Oxford Biomed Res Unit, Nuffield Dept Orthoped Rheumatol & Musculoskeleta, Oxford OX3 7LD, England
基金
英国惠康基金; 英国生物技术与生命科学研究理事会;
关键词
LINKED MENTAL-RETARDATION; JMJD2; FAMILY; ANDROGEN RECEPTOR; JUMONJI-DOMAIN; JARID1C GENE; PHF8; METHYLATION; MUTATIONS; HYPOXIA; SPECIFICITY;
D O I
10.1074/jbc.M111.283689
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
N-epsilon-Methylations of histone lysine residues play critical roles in cell biology by "marking" chromatin for transcriptional activation or repression. Lysine demethylases reverse Art-methylation in a sequence- and rnethylation-selective manner. The determinants of sequence selectivity for histone demethylases have been unclear. The human JMJD2 (KDM4) H3K9 and H3K36 demethylases can be divided into members that act on both H3K9 and H3K36 and H3K9 alone. Kinetic, crystallographic, and mutagenetic studies in vitro and in cells on KDM4A-E reveal that selectivity is determined by multiple interactions within the catalytic domain but outside the active site. Structurally informed phylogenetic analyses reveal that KDM4A-C orthologues exist in all genome-sequenced vertebrates with earlier animals containing only a single KDM4 enzyme. KDM4D orthologues only exist in eutherians (placental mammals) where they are conserved, including proposed substrate sequence-determining residues. The results will be useful for the identification of inhibitors for specific histone demethylases.
引用
收藏
页码:41616 / 41625
页数:10
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