生物谷報(bào)道：來自美Jewish國立醫(yī)療研究中心（National Jewish Medical and Research Center）,，中國農(nóng)業(yè)大學(xué)生物科學(xué)學(xué)院,，霍華德休斯醫(yī)學(xué)院，清華大學(xué)與中國醫(yī)學(xué)科學(xué)院（中國協(xié)和醫(yī)科大學(xué)）醫(yī)學(xué)分子生物學(xué)國家重點(diǎn)實(shí)驗(yàn)室（National Key Laboratory of Medical Molecular Biology）等處的研究人員通過獲得JHDM3A催化核心與甲基化H3K36多肽底物的復(fù)合結(jié)晶結(jié)構(gòu),，加深了對(duì)組蛋白去甲基化的機(jī)制及特異性的了解,。這一研究成果公布在《美國國家科學(xué)院院刊》（PNAS）網(wǎng)絡(luò)版上,。
文章的通訊作者是來自Jewish國立醫(yī)療研究中心的John Kappler,，及張公義（Gongyi Zhang，音譯）博士,，后者早年于中科院生物物理所獲得博士學(xué)位,。
在基因組中除了DNA和RNA序列以外，還有許多調(diào)控基因的信息,，它們雖然本身不改變基因的序列,，但是可以通過基因修飾，蛋白質(zhì)與蛋白質(zhì),、DNA和其它分子的相互作用,，而影響和調(diào)節(jié)遺傳基因的功能和特性，并且通過細(xì)胞分裂和增殖周期影響遺傳,，科學(xué)家們將這一種遺傳方式稱為表觀遺傳學(xué)（epigenetics）,。
組蛋白甲基化是表觀遺傳修飾方式中的一種，參與了異染色質(zhì)的形成,、基因印記,、染色體失活和基因轉(zhuǎn)錄調(diào)控等，其中jumonji C (JmjC)位點(diǎn)是介導(dǎo)組蛋白賴氨酸去甲基化的一個(gè)催化位點(diǎn),。
在這篇文章中,，研究人員獲得了JHDM3A（jumonji C (JmjC)-domain-containing histone demethylase 3A，也稱為JMJD2A）催化核心與甲基化H3K36多肽底物的復(fù)合結(jié)晶結(jié)構(gòu),，從中研究人員發(fā)現(xiàn)JMJD2A和多肽之間的相互作用是這個(gè)酶和多肽的主要部分,。另外多肽結(jié)合的特異性主要是由多肽的的初級(jí)結(jié)構(gòu)決定的，也就解釋了JMJD2A對(duì)于H3K8和H3K36具有特異性,，而對(duì)其它甲基化殘基,，譬如H3K27沒有這種特異性。
除此之外，研究人員還發(fā)現(xiàn)一種特殊的甲基化基團(tuán)的特異性是受到多因素影響的,，比如酶催化中心的空間,，及靜電環(huán)境等。這些都有助于我們加深對(duì)組蛋白去甲基化的機(jī)制及特異性的了解,。
原始出處:
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
