Journal Article

Basis of the H2AK119 specificity of the Polycomb repressive deubiquitinase

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

2023

Overview

Repression of gene expression by protein complexes of the Polycomb group is a fundamental mechanism that governs embryonic development and cell-type specification 1 – 3 . The Polycomb repressive deubiquitinase (PR-DUB) complex removes the ubiquitin moiety from monoubiquitinated histone H2A K119 (H2AK119ub1) on the nucleosome 4 , 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 – 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. The cryo-electron microscopy structure of the Polycomb repressive deubiquitinase (PR-DUB) in complex with the H2AK119ub1 nucleosome provides insight into how the substrate specificity of PR-DUB is achieved.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/1 / 101/28 / 13 / 38 / 38/91 / 631/337/176 / 631/535/1258 / 82 / 82/16 / 82/80 / 82/83 / Binding / Catalytic Domain / Cryoelectron Microscopy / Deubiquitinating Enzymes - classification / Deubiquitinating Enzymes - metabolism / Deubiquitinating Enzymes - ultrastructure / DNA methylation / Electron microscopy / Embryogenesis / Embryonic growth stage / Gene expression / Gene silencing / Genes / Histone H2A / Histones / Histones - chemistry / Histones - metabolism / Humanities and Social Sciences / Humans / Insects / Microscopy / multidisciplinary / Mutation / Nucleosomes - chemistry / Nucleosomes - genetics / Nucleosomes - metabolism / Peptides / Polycomb group proteins / Polycomb Repressive Complex 1 - chemistry / Polycomb Repressive Complex 1 - metabolism / Polycomb Repressive Complex 1 - ultrastructure / Polycomb-Group Proteins - chemistry / Polycomb-Group Proteins - metabolism / Polycomb-Group Proteins - ultrastructure / Proteins / Repressor Proteins - chemistry / Repressor Proteins - metabolism / Repressor Proteins - ultrastructure / Science / Science (multidisciplinary) / Substrate Specificity / Substrates / Ubiquitin / Ubiquitin - metabolism / Ubiquitin Thiolesterase - chemistry / Ubiquitin Thiolesterase - metabolism / Ubiquitin Thiolesterase - ultrastructure / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - chemistry / Ubiquitin-Protein Ligases - metabolism / Ubiquitin-Protein Ligases - ultrastructure / Ubiquitination