Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase
Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase
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DOI：
10.1038/nsmb1273
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发表时间：
2007-08-01
影响因子：
16.8
通讯作者：
Trievel, Raymond C.
中科院分区：
文献类型：
--
作者：
Couture, Jean-Francois;Collazo, Evys;Trievel, Raymond C.
JMJD 2A是一种JmjC组蛋白脱甲基酶（HDM），催化组蛋白H3（H3 K9 me 2/3和H3 K36 me 2/3）中二甲基化和三甲基化Lys 9和Lys 36的脱甲基化。在这里，我们呈现了与H3 K9 me 3、H3 K36 me 2和H3 K36 me 3肽复合的JMJD 2A催化结构域的晶体结构。这些结构揭示了组蛋白底物是通过骨架氢键和疏水相互作用的网络来识别的，该网络将三甲基赖氨酸存款到活性位点。三甲基化的ε-铵阳离子通过碳-氧（CH中心点中心点O）氢键在甲基铵结合口袋内配位，该氢键将ζ-甲基中的一个定位在Fe（II）中心附近以进行羟基化和去甲基化。包含该口袋的残基的突变消除了JMJD 2A的去甲基化，除了S288 A取代，其增强活性，特别是对H3 K9 me 2。我们提出，这个残基调节JMJD 2酶和其他三甲基赖氨酸特异性JmjC HDMs的甲基化状态特异性。
JMJD2A is a JmjC histone demethylase (HDM) that catalyzes the demethylation of di- and trimethylated Lys9 and Lys36 in histone H3 (H3K9me2/3 and H3K36me2/3). Here we present the crystal structures of the JMJD2A catalytic domain in complex with H3K9me3, H3K36me2 and H3K36me3 peptides. The structures reveal that histone substrates are recognized through a network of backbone hydrogen bonds and hydrophobic interactions that deposit the trimethyllysine into the active site. The trimethylated epsilon-ammonium cation is coordinated within a methylammonium-binding pocket through carbon-oxygen (CH center dot center dot center dot O) hydrogen bonds that position one of the zeta-methyl groups adjacent to the Fe(II) center for hydroxylation and demethylation. Mutations of the residues comprising this pocket abrogate demethylation by JMJD2A, with the exception of an S288A substitution, which augments activity, particularly toward H3K9me2. We propose that this residue modulates the methylation-state specificities of JMJD2 enzymes and other trimethyllysine-specific JmjC HDMs.