Structure-function analysis reveals a novel mechanism for regulation of histone demethylase LSD2/AOF1/KDM1b
Structure-function analysis reveals a novel mechanism for regulation of histone demethylase LSD2/AOF1/KDM1b
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结构功能分析揭示了组蛋白去甲基化酶LSD2/AOF1/KDM1b调节的新机制
DOI：
10.1038/cr.2012.177
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发表时间：
2012-12
期刊：
影响因子：
44.1
通讯作者：
陈忠周
中科院分区：
文献类型：
--
作者：
陈忠周
LSD2/AOF1/KDM1b催化单甲基化和双甲基化H3K4的去甲基化，在转录调控和基因组印迹中发挥重要作用。在这里，我们报道了载脂蛋白LSD2和LSD2与模仿H3K4me2的肽复合物的高分辨率晶体结构。LSD2的三个结构域，即新颖的n端锌指结构域、位于中心的swm结构域和c端氧化酶结构域紧密地聚集在一起，形成靴状结构。氧化酶结构域的活性位点空腔足够大，可以容纳组蛋白H3尾部的几个残基，并且不能区分H3K4甲基化的不同状态。n端锌指结构域由一种新型的c4h2c2型锌指和一种特殊的cw型锌指组成，是去甲基化酶活性和辅因子黄素腺嘌呤二核苷酸（FAD）结合所必需的。事实上，LSD2去甲基化酶活性和FAD的结合需要通过锌指- srim氧化酶结构域进行广泛的相互作用。这些结果揭示了锌指结构域和swm结构域控制LSD2去甲基酶活性的新机制，并为阐明LSD2的调控和功能提供了框架。
LSD2/AOF1/KDM1b catalyzes demethylation of mono-and di-methylated H3K4 and plays an important role in transcriptional regulation and genomic imprinting. Here, we report the high-resolution crystal structures of apo-LSD2 and LSD2 in complex with a peptide that mimics H3K4me2. Three structural domains of LSD2, namely, the novel N-terminal zinc finger, the centrally located SWIRM domain, and the C-terminal oxidase domain, closely pack together to form a boot-shaped structure. The active site cavity in the oxidase domain is large enough to accommodate several residues of the histone H3 tail and cannot discriminate between the different states of H3K4 methylation. The N-terminal zinc-finger domain, composed of a novel C4H2C2-type zinc finger and a specific CW-type zinc finger, is required for demethylase activity and, surprisingly, the binding of cofactor flavin adenine dinucleotide (FAD). In fact, a relay of extensive interactions through the zinc finger-SWIRM-oxidase domains is required for LSD2 demethylase activity and the binding of FAD. These results reveal a novel mechanism for the zinc finger and SWIRM domains in controlling LSD2 demethylase activity and provide a framework for elucidating the regulation and function of LSD2.
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