PR-DUB的结构和功能研究:其特异性H2AK119去泛素化活性的分子机制

中国科学：生命科学 Pub Date : 2023-07-01 DOI:10.1360/ssv-2023-0057

Ni Wang, Xudong Wu

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摘要

Transcriptional inhibitory chromatin state is an important epigenetic regulatory mechanism that finely regulates the correct spatiotemporal expression of developmental genes and determines the fate of cells. Its imbalance leads to various diseases such as tumors PcG proteins often form complexes to regulate histone modifications, with PRC1 catalyzing H2AK119 monoubiquitination (H2AK119ub1), PRC2 catalyzing H3K27 methylation (H3K27me), and PR-DUB removing H2AK119ub1 At present, the mechanism of action and structural basis of PRC1 and PRC2 are relatively clear, but little is known about PR-DUB H2AK119ub1 modification is the earliest discovered type of histone modification, which is indispensable for recruiting PRC2, depositing H3K27me3, enhancing PRC stability, and inhibiting the formation of advanced chromatin structures PR-DUB restricts the distribution and level of H2AK119ub1 in the genome by antagonizing PRC1 enzyme activity, thereby preventing the silencing of active genes and ensuring that PRC1 can stably exert inhibitory effects within the multi combed chromatin domain The mammalian PR-DUB complex binds to ASXL1/2 or 3 through a multi protein core composed of BAP1 and helper proteins such as HCFC1 and FOXK1/2 BAP1 is a ubiquitin hydrolase, but its activity depends on binding to the DEUBAD domain of ASXL protein When using free histones and peptides as substrates, PR-DUB can be de ubiquitinated indiscriminately, but its catalytic activity against nucleosome substrates is H2AK119 specific Previously, through the crystal structure analysis of Drosophila PR-DUB, the M ü ller team discovered a mechanism by which ASX increases the ubiquitin affinity of the BAP1 Drosophila homolog Calypso to mediate activation. Calypso ULD-Asx DEU interacts to form a complete ubiquitin binding pocket, but there is still a lack of structural analysis of PR-DUB binding to nucleosome substrates, and the factors determining the specific removal of H2AK119ub dependent on nucleosomes are still unclear Recently, Xu Ruiming, Zhu Bing, Institute of Biophysics, Chinese Academy of Sciences

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Structural and functional studies of PR-DUB: molecular mechanism of its specific H2AK119 deubiquitination activity

导的转录抑制性染色质状态是一种重要的表观遗传调控机制, 精细调控发育基因的正确时空表达和细胞的命运决定, 其失调导致肿瘤等多种疾病. PcG蛋白往往形成复合物调控组蛋白修饰 , 其中PRC1催化 H2AK119单泛素化(H2AK119ub1), PRC2催化H3K27 甲基化(H3K27me), PR-DUB去除H2AK119ub1. 目前, PRC1和PRC2的作用机制和结构学基础已经比较清楚, 而对PR-DUB还知之甚少. H2AK119ub1修饰是发现最早的一类组蛋白修饰, 对于募集PRC2、沉积H3K27me3、增强PRC稳定性以及抑制性染色质高级结构形成均不可或缺 . PR-DUB 通过拮抗PRC1酶活性, 限制基因组的H2AK119ub1分布和水平, 从而防止活性基因被沉默, 也确保PRC1 能在多梳染色质域内稳定地发挥抑制作用 . 哺乳动物PR-DUB复合物通过由BAP1和辅助蛋白如HCFC1 和FOXK1/2组成的多蛋白核心与ASXL1/2或3结合. 其中BAP1是泛素水解酶, 但其酶活性依赖与ASXL蛋白的DEUBAD结构域结合. 以游离组蛋白和肽为底物时, PR-DUB可以不加区分地去泛素化, 但其对核小体底物的催化活性却是H2AK119特异的. 此前, 通过果蝇PR-DUB的晶体结构解析, Müller团队发现了 ASX增加BAP1果蝇同源物Calypso的泛素亲和力以介导激活的机制, 其中Calypso ULD-Asx DEU相互作用而形成一个完整的泛素结合口袋, 但是仍然缺乏对结合核小体底物的PR-DUB的结构分析, 决定核小体依赖的H2AK119ub特异去除的因素尚不清楚. 近日, 中国科学院生物物理研究所许瑞明、朱冰

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