生物谷报道：来自美Jewish国立医疗研究中心（National Jewish Medical and Research Center），中国农业大学生物科学学院，霍华德休斯医学院，清华大学与中国医学科学院（中国协和医科大学）医学分子生物学国家重点实验室（National Key Laboratory of Medical Molecular Biology）等处的研究人员通过获得JHDM3A催化核心与甲基化H3K36多肽底物的复合结晶结构，加深了对组蛋白去甲基化的机制及特异性的了解。这一研究成果公布在《美国国家科学院院刊》（PNAS）网络版上。
文章的通讯作者是来自Jewish国立医疗研究中心的John Kappler，及张公义（Gongyi Zhang，音译）博士，后者早年于中科院生物物理所获得博士学位。
在基因组中除了DNA和RNA序列以外，还有许多调控基因的信息，它们虽然本身不改变基因的序列，但是可以通过基因修饰，蛋白质与蛋白质、DNA和其它分子的相互作用，而影响和调节遗传基因的功能和特性，并且通过细胞分裂和增殖周期影响遗传，科学家们将这一种遗传方式称为表观遗传学（epigenetics）。
组蛋白甲基化是表观遗传修饰方式中的一种，参与了异染色质的形成、基因印记、染色体失活和基因转录调控等，其中jumonji C (JmjC)位点是介导组蛋白赖氨酸去甲基化的一个催化位点。
在这篇文章中，研究人员获得了JHDM3A（jumonji C (JmjC)-domain-containing histone demethylase 3A，也称为JMJD2A）催化核心与甲基化H3K36多肽底物的复合结晶结构，从中研究人员发现JMJD2A和多肽之间的相互作用是这个酶和多肽的主要部分。另外多肽结合的特异性主要是由多肽的的初级结构决定的，也就解释了JMJD2A对于H3K8和H3K36具有特异性，而对其它甲基化残基，譬如H3K27没有这种特异性。
除此之外，研究人员还发现一种特殊的甲基化基团的特异性是受到多因素影响的，比如酶催化中心的空间，及静电环境等。这些都有助于我们加深对组蛋白去甲基化的机制及特异性的了解。
原始出处:
Published online before print June 13, 2007, 10.1073/pnas.0704525104
PNAS | June 26, 2007 | vol. 104 | no. 26 | 10818-10823
OPEN ACCESS ARTICLE
Structural basis of the recognition of a methylated histone tail by JMJD2A
Zhongzhou Chen*,, Jianye Zang*, John Kappler*,,, Xia Hong*, Frances Crawford*,, Qin Wang*, Fei Lan¶, Chengyu Jiang||, Johnathan Whetstine¶, Shaodong Dai*,, Kirk Hansen**, Yang Shi¶, and Gongyi Zhang*,**,
*Department of Immunology, National Jewish Medical and Research Center, Denver, CO 80206; College of Biological Sciences, China Agricultural University, Beijing 100094, China; Howard Hughes Medical Institute, National Jewish Medical and Research Center, Denver, CO 80206; ¶Department of Pathology, Harvard Medical School, Boston, MA 02115; ||National Key Laboratory of Medical Molecular Biology, Peking union Medical College, Tsinghua University and Chinese Academy of Medical Sciences, Beijing 100084, China; and **Department of Pharmacology and Cancer Center, School of Medicine, University of Colorado Health Sciences Center, Aurora, CO 80045
Contributed by John Kappler, May 14, 2007 (received for review May 2, 2007)
The Jumonji C domain is a catalytic motif that mediates histone lysine demethylation. The Jumonji C-containing oxygenase JMJD2A specifically demethylates tri- and dimethylated lysine-9 and lysine-36 of histone 3 (H3K9/36me3/2). Here we present structures of the JMJD2A catalytic core complexed with methylated H3K36 peptide substrates in the presence of Fe(II) and N-oxalylglycine. We found that the interaction between JMJD2A and peptides largely involves the main chains of the enzyme and the peptide. The peptide-binding specificity is primarily determined by the primary structure of the peptide, which explains the specificity of JMJD2A for methylated H3K9 and H3K36 instead of other methylated residues such as H3K27. The specificity for a particular methyl group, however, is affected by multiple factors, such as space and the electrostatic environment in the catalytic center of the enzyme. These results provide insights into the mechanisms and specificity of histone demethylation.
demethylase | oxygenase | JmjC | epigenetic | chromatin
