Stavropoulos Pete, Blobel Günter, Hoelz André
Laboratory of Cell Biology, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Nat Struct Mol Biol. 2006 Jul;13(7):626-32. doi: 10.1038/nsmb1113. Epub 2006 Jun 25.
The reversible methylation of specific lysine residues in histone tails is crucial in epigenetic gene regulation. LSD1, the first known lysine-specific demethylase, selectively removes monomethyl and dimethyl, but not trimethyl modifications of Lys4 or Lys9 of histone-3. Here, we present the crystal structure of LSD1 at 2.9-A resolution. LSD1 forms a highly asymmetric, closely packed domain structure from which a long helical 'tower' domain protrudes. The active site cavity is spacious enough to accommodate several residues of the histone tail substrate, but does not appear capable of recognizing the different methylation states of the substrate lysine. This supports the hypothesis that trimethylated lysine is chemically rather than sterically discriminated. We present a biochemical analysis of LSD1 mutants that identifies crucial residues in the active site cavity and shows the importance of the SWIRM and tower domains for catalysis.
组蛋白尾部特定赖氨酸残基的可逆甲基化在表观遗传基因调控中至关重要。LSD1是首个被发现的赖氨酸特异性去甲基化酶，它可选择性去除组蛋白H3赖氨酸4或赖氨酸9上的一甲基化和二甲基化修饰，但不能去除三甲基化修饰。在此，我们展示了分辨率为2.9埃的LSD1晶体结构。LSD1形成了一个高度不对称、紧密堆积的结构域，从中伸出一个长螺旋“塔”结构域。活性位点腔足够宽敞，能够容纳组蛋白尾底物的几个残基，但似乎无法识别底物赖氨酸的不同甲基化状态。这支持了三甲基化赖氨酸是通过化学而非空间方式被区分的假说。我们对LSD1突变体进行了生化分析，确定了活性位点腔中的关键残基，并显示了SWIRM和塔结构域对催化作用的重要性。
