A partially disordered region connects gene repression and activation functions of EZH2
A partially disordered region connects gene repression and activation functions of EZH2
复制标题
DOI：
10.1073/pnas.1914866117
复制
发表时间：
2020-07-21
影响因子：
11.1
通讯作者：
Liu, Xin
中科院分区：
文献类型：
--
作者：
Jiao, Lianying;Shubbar, Murtada;Liu, Xin
Zeste增强子同源物2（EZH 2）是Polycomb抑制复合物2（PRC 2）的催化亚基，其最低限度地需要两个其他亚基EED和SUZ 12来实现酶活性。传统上已知EZH 2介导组蛋白H3 K27三甲基化，这是沉默染色质的标志。新出现的证据表明，EZH 2还在与典型PRC 2不同的背景下激活癌细胞中的基因表达。EZH 2从基因阻遏物到激活物的功能转换的分子机制尚不清楚。在这里，我们表明，EZH 2窝藏一个隐藏的，部分无序的反式激活结构域（EZH）能够与活跃的转录机制，模仿原型酸性激活剂的组件相互作用。EZH 2 β包含通常参与H3 K27甲基化的SRM（刺激响应基序）和SANT 1（SWI 3、ADA 2、N-CoR和TFIIIB 1）区域。EZH 2-EED二元复合物的晶体结构表明，EZH 2 β在非经典PRC 2背景下介导蛋白质寡聚化，并被完全隔离。EZH 2激酶可以通过癌症特异性EZH 2磷酸化事件解锁，以经历结构转变，这可以使随后的转录共激活因子结合成为可能。EZH 2 β直接与转录辅激活因子和组蛋白乙酰转移酶p300相互作用，并以p300依赖性方式激活细胞中的基因表达。EZH 1是EZH 2的代理基因，EZH 1的基因激活功能也可能与EZH 2的基因激活功能有关。已知在癌细胞中将EZH 2异常转化为基因激活剂的独特激酶信号传导途径现在可以在EZH 2激酶的共同结构背景中理解。
Enhancer of Zeste Homolog 2 (EZH2) is the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), which minimally requires two other subunits, EED and SUZ12, for enzymatic activity. EZH2 has been traditionally known to mediate histone H3K27 trimethy-lation, a hallmark of silent chromatin. Emerging evidence indicates that EZH2 also activates gene expression in cancer cells in a context distinct from canonical PRC2. The molecular mechanism underlying the functional conversion of EZH2 from a gene re-pressor to an activator is unclear. Here, we show that EZH2 harbors a hidden, partially disordered transactivation domain (TAD) capable of interacting with components of active transcrip-tion machinery, mimicking archetypal acidic activators. The EZH2 TAD comprises the SRM (Stimulation-Responsive Motif) and SANT1 (SWI3, ADA2, N-CoR, and TFIIIB 1) regions that are normally involved in H3K27 methylation. The crystal structure of an EZH2-EED binary complex indicates that the EZH2 TAD mediates protein oligomerization in a noncanonical PRC2 context and is en-tirely sequestered. The EZH2 TAD can be unlocked by cancer -specific EZH2 phosphorylation events to undergo structural tran-sitions that may enable subsequent transcriptional coactivator binding. The EZH2 TAD directly interacts with the transcriptional coactivator and histone acetyltransferase p300 and activates gene expression in a p300-dependent manner in cells. The correspond-ing TAD may also account for the gene activation function of EZH1, the paralog of EZH2. Distinct kinase signaling pathways that are known to abnormally convert EZH2 into a gene activator in cancer cells can now be understood in a common structural con-text of the EZH2 TAD.