Crystal structure of the histone lysine specific demethylase LSD1 complexed with tetrahydrofolate
Crystal structure of the histone lysine specific demethylase LSD1 complexed with tetrahydrofolate
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DOI：
10.1002/pro.2469
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发表时间：
2014-07-01
期刊：
影响因子：
8
通讯作者：
Wagner, Conrad
中科院分区：
文献类型：
--
作者：
Luka, Zigmund;Pakhomova, Svetlana;Wagner, Conrad
一个重要的表观遗传修饰是组蛋白赖氨酸残基的甲基化/去甲基化。第一个被发现的组蛋白去甲基化酶是赖氨酸特异性去甲基化酶1 LSD1，这是一种含有黄素的酶，它在组蛋白H3中进行二甲基赖氨酸和单甲基赖氨酸4的去甲基化。除去的甲基被氧化成甲醛。该反应类似于二甲基甘氨酸脱氢酶和肌氨酸脱氢酶的反应，其中蛋白质结合的四氢叶酸（THF）被提议作为生成甲醛的受体。我们之前已经证明LSD1与THF具有高亲和力，这表明它可能参与组蛋白去甲基化反应。在细胞中，LSD1与co-repressor element 1 silencing transcription factor （CoREST）相互作用。为了阐明叶酸在去甲基化反应中的作用，我们解析了LSD1-CoREST-THF配合物的晶体结构。在复合物中，叶酸结合位点位于黄素腺嘌呤二核苷酸附近的活性中心。叶酸的这种位置表明，结合的THF接受组蛋白去甲基化过程中产生的甲醛，形成5,10-亚甲基THF。我们还通过质谱分析显示了在THF存在的酶促反应过程中5,10-亚甲基THF的形成。这种形式的叶酸的产生可以防止潜在的有毒甲醛在细胞中的积累。这些研究表明，叶酸除了在代谢过程中发挥单碳单位转移的传统作用外，还可能在基因表达的表观遗传控制中发挥作用。
An important epigenetic modification is the methylation/demethylation of histone lysine residues. The first histone demethylase to be discovered was a lysine-specific demethylase 1, LSD1, a flavin containing enzyme which carries out the demethylation of di- and monomethyllysine 4 in histone H3. The removed methyl groups are oxidized to formaldehyde. This reaction is similar to those performed by dimethylglycine dehydrogenase and sarcosine dehydrogenase, in which protein-bound tetrahydrofolate (THF) was proposed to serve as an acceptor of the generated formaldehyde. We showed earlier that LSD1 binds THF with high affinity which suggests its possible participation in the histone demethylation reaction. In the cell, LSD1 interacts with co-repressor for repressor element 1 silencing transcription factor (CoREST). In order to elucidate the role of folate in the demethylating reaction we solved the crystal structure of the LSD1-CoREST-THF complex. In the complex, the folate-binding site is located in the active center in close proximity to flavin adenine dinucleotide. This position of the folate suggests that the bound THF accepts the formaldehyde generated in the course of histone demethylation to form 5,10-methylene-THF. We also show the formation of 5,10-methylene-THF during the course of the enzymatic reaction in the presence of THF by mass spectrometry. Production of this form of folate could act to prevent accumulation of potentially toxic formaldehyde in the cell. These studies suggest that folate may play a role in the epigenetic control of gene expression in addition to its traditional role in the transfer of one-carbon units in metabolism.