小柯机器人

近日，中国科学院生物物理研究所许瑞明等研究人员合作揭示去泛素化酶复合物特异性去除核小体H2AK119泛素化的分子机制。该项研究成果于2023年3月29日在线发表在《自然》杂志上。

研究人员表示，Polycomb的蛋白复合物对基因表达的抑制是支配胚胎发育和细胞类型特化的一个基本机制。Polycomb repressive deubiquitinase（PR-DUB）复合物从核糖体上的单泛素化组蛋白H2A K119（H2AK119ub1）中去除泛素分子，抵消了Polycomb repressive complex 1（PRC1）的泛素E3连接酶活性，促进Polycomb蛋白对基因的正确沉默，保护活性基因不被PRC1无意中沉默。PR-DUB错综复杂的生物学功能需要准确地靶向H2AK119ub1，但PR-DUB可以不加选择地去泛素化游离组蛋白和多肽底物；因此其精致的核糖体依赖性底物特异性的基础仍不清楚。

研究人员报告了人类PR-DUB的冷冻电镜结构，它由BAP1和ASXL1组成，与染色体复合。研究人员发现ASXL1指导BAP1带正电的C端延伸部分与核糖体DNA和组蛋白H3-H4的结合，这是它在形成泛素结合裂隙中的作用。此外，BAP1催化结构域的一个保守环段位于H2A-H2B的酸性斑块附近。这种独特的核糖体结合模式使H2A的C端尾巴从核糖体表面移开，并使PR-DUB对H2AK119ub1具有特异性。

附：英文原文

Title: Basis of the H2AK119 specificity of the Polycomb repressive deubiquitinase

Author: Ge, Weiran, Yu, Cong, Li, Jingjing, Yu, Zhenyu, Li, Xiaorong, Zhang, Yan, Liu, Chao-Pei, Li, Yingfeng, Tian, Changlin, Zhang, Xinzheng, Li, Guohong, Zhu, Bing, Xu, Rui-Ming

Issue&Volume: 2023-03-29

Abstract: Repression of gene expression by protein complexes of the Polycomb group is a fundamental mechanism that governs embryonic development and cell-type specification1,2,3. The Polycomb repressive deubiquitinase (PR-DUB) complex removes the ubiquitin moiety from monoubiquitinated histone H2A K119 (H2AK119ub1) on the nucleosome4, counteracting the ubiquitin E3 ligase activity of Polycomb repressive complex 1 (PRC1)5 to facilitate the correct silencing of genes by Polycomb proteins and safeguard active genes from inadvertent silencing by PRC1 (refs. 6,7,8,9). The intricate biological function of PR-DUB requires accurate targeting of H2AK119ub1, but PR-DUB can deubiquitinate monoubiquitinated free histones and peptide substrates indiscriminately; the basis for its exquisite nucleosome-dependent substrate specificity therefore remains unclear. Here we report the cryo-electron microscopy structure of human PR-DUB, composed of BAP1 and ASXL1, in complex with the chromatosome. We find that ASXL1 directs the binding of the positively charged C-terminal extension of BAP1 to nucleosomal DNA and histones H3–H4 near the dyad, an addition to its role in forming the ubiquitin-binding cleft. Furthermore, a conserved loop segment of the catalytic domain of BAP1 is situated near the H2A–H2B acidic patch. This distinct nucleosome-binding mode displaces the C-terminal tail of H2A from the nucleosome surface, and endows PR-DUB with the specificity for H2AK119ub1.

DOI: 10.1038/s41586-023-05841-y

Source: https://www.nature.com/articles/s41586-023-05841-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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