Crystal Structure and Functional Analysis of JMJD5 Indicate an Alternate Specificity and Function
Crystal Structure and Functional Analysis of JMJD5 Indicate an Alternate Specificity and Function
复制标题
DOI：
10.1128/mcb.00513-12
复制
发表时间：
2012-10-01
影响因子：
5.3
通讯作者：
Trievel, Raymond C.
中科院分区：
文献类型：
--
作者：
Del Rizzo, Paul A.;Krishnan, Swathi;Trievel, Raymond C.
JMJD5是一种Jumonji C(JmjC)蛋白，参与乳腺癌的发生、昼夜节律调节、胚胎发育和破骨细胞的形成。最近，JMJD5(也称为KDM8)被报道使组蛋白H3(H3K36me2)中的二甲基化Lys-36去甲基化，调节控制细胞周期进程的基因。在这里，我们报道了人JMJD5催化结构域与底物2-氧戊二酸(2-OG)和抑制剂N-草甘氨酸(NOG)的高分辨晶体结构。这些结构显示了一个在JmjC家族中保守的贝塔桶折叠，以及一个通向酶活性部位的长而浅的裂隙。与其他JmjC酶的比较表明，JMJD5与天冬酰胺和组氨酸羟基酶FIH-1(缺氧抑制因子1[HIF-1])、赖氨酰羟基酶JMJD6和RNA羟基酶TYW5有序列和结构上的同源性，但与JmjC赖氨酸去甲基酶(KDM)的同源性有限。与以前的发现相反，生化分析表明，JMJD5对甲基化的H3K36或对组蛋白H3和H4的N端的其他甲基赖氨酸没有去甲基酶活性。综上所述，这些结果表明JMJD5参与了独立于组蛋白去甲基化的作用，并可能作为一种蛋白质羟基酶发挥作用，因为它与FIH-1和JMJD6结构上的同源性。
JMJD5 is a Jumonji C (JmjC) protein that has been implicated in breast cancer tumorigenesis, circadian rhythm regulation, embryological development, and osteoclastogenesis. Recently, JMJD5 (also called KDM8) has been reported to demethylate dimethylated Lys-36 in histone H3 (H3K36me2), regulating genes that control cell cycle progression. Here, we report high-resolution crystal structures of the human JMJD5 catalytic domain in complex with the substrate 2-oxoglutarate (2-OG) and the inhibitor N-oxalylglycine (NOG). The structures reveal a beta-barrel fold that is conserved in the JmjC family and a long shallow cleft that opens into the enzyme's active site. A comparison with other JmjC enzymes illustrates that JMJD5 shares sequence and structural homology with the asparaginyl and histidinyl hydroxylase FIH-1 (factor inhibiting hypoxia-inducible factor 1 [ HIF-1]), the lysyl hydroxylase JMJD6, and the RNA hydroxylase TYW5 but displays limited homology to JmjC lysine demethylases (KDMs). Contrary to previous findings, biochemical assays indicate that JMJD5 does not display demethylase activity toward methylated H3K36 nor toward the other methyllysines in the N-terminal tails of histones H3 and H4. Together, these results imply that JMJD5 participates in roles independent of histone demethylation and may function as a protein hydroxylase given its structural homology with FIH-1 and JMJD6.