摘要
Histone 离氨酸 methylation 能被 JmjC 包含域的蛋白质在 sequence-state-specific 和 methylation-state-specific 举止移开。然而，底层特性怎么样，决定，酶怎么被调整，大部分是未知的。我们最近发现了那 ceKDM7A，一个哲学博士 -- 并且 JmjC 包含域的蛋白质，是为 H3K9me2 特定的 histone demethylase， H3K27me2，和 PHD 摸绑定到 H3K4me3 指南在 vivo 的 demethylation 活动。为了为酶的活动和 PHD 的功能提供结构的卓见进分子的机制，摸，我们与包含 H3K4me3， H3K9me2，和 H3K27me2 修正的各种各样的联合的单身者或二肽一起在 apo 形式并且在建筑群解决了酶的六水晶结构。结构显示 H3K9me2 和 H3K27me2 以一种类似的方式与 ceKDM7A 交往，并且肽绑定特性被特定的相互作用的一个网络决定。结构的几何测量也揭示了与 PHD 手指和 H3K9me2 界限联系到 JmjC 领域的那 H3K4me3 从二个分开的分子，建议 trans-histone 肽绑定机制。因此，我们的全身的结构的研究重要地由催化领域而且更多揭示底层识别不仅，为 H3K9me2 和 H3K27me2 的 ceDKM7A 的双特性的分子的机制。
Histone lysine methylation can be removed by JmjC domain-containing proteins in a sequence- and methylationstate-specific manner. However, how substrate specificity is determined and how the enzymes are regulated were largely unknown. We recently found that ceKDM7A, a PHD- and JmjC domain-containing protein, is a histone demethylase specific for H3K9me2 and H3K27me2, and the PHD finger binding to H3K4me3 guides the demethylation activity in vivo. To provide structural insight into the molecular mechanisms for the enzymatic activity and the function of the PHD finger, we solved six crystal structures of the enzyme in apo form and in complex with single or two peptides containing various combinations of H3K4me3, H3K9me2, and H3K27me2 modifications. The structures indicate that H3Kgme2 and H3K27me2 interact with ceKDMTA in a similar fashion, and that the peptide-binding specificity is determined by a network of specific interactions. The geometrical measurement of the structures also revealed that H3K4me3 associated with the PHD finger and H3K9me2 bound to the JmjC domain are from two separate molecules, suggesting a trans-histone peptide-binding mechanism. Thus, our systemic structural studies reveal not only the substrate recognition by the catalytic domain but also more importantly, the molecular mechanism of dual specifieity of ceDKM7A for both H3K9me2 and H3K27me2.
