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<p>Protein ubiquitination critically regulates biological processes through both proteolytic and nonproteolytic mechanisms. While classically known for protein degradation, ubiquitination also modulates enzymatic activity. However, current mechanisms of ubiquitination-mediated enzymatic modulation are spatially constrained near enzyme–substrate interfaces. Here, we report a unique ubiquitination-mediated regulatory paradigm that activates the Polycomb repressive deubiquitinase (PR-DUB) complex from a site distal to the enzyme–substrate interface. We found that ASXL1 K351 monoubiquitination promotes nucleosomal H2AK119Ub deubiquitination by stabilizing the PR-DUB catalytic pocket, thereby increasing catalytic velocity (<i>V</i><sub>max</sub>) without affecting substrate affinity (<i>K</i><sub>m</sub>). Structurally, ubiquitin at ASXL1 K351 bridges the BAP1 and ASXL1 subunits, functioning as a cross-bracing ‘glue’ that constrains their conformational dynamics without altering the nucleosome-binding interface. Molecular dynamics and hydrogen–deuterium exchange mass spectrometry revealed that this modification locks PR-DUB in a catalytic state poised for substrate cleavage. This study reveals a unique ubiquitin function of intersubunit fastening through a molecular glue effect and clarifies the mechanism of PR-DUB activation.</p><p></p>

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Unique gluing effect of ASXL1 K351 monoubiquitination stimulates the PR-DUB activity

  • 期刊论文

  • 发表日期：

    2026年1月9日

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  • Tianyi Zhang,
  • Jiqing Zheng,
  • Zebing Tong,
  • Zhiheng Deng,
  • Zaozhen He,
  • Xiangwei Wu,
  • Miao Wang,
  • Yunxiang Du,
  • Ziyu Xu,
  • Shixian Tao,
  • Shizhang Wan,
  • Xiaolin Tian,
  • Haiteng Deng,
  • Man Pan,
  • Huasong Ai,
  • Lei Liu

摘要

Protein ubiquitination critically regulates biological processes through both proteolytic and nonproteolytic mechanisms. While classically known for protein degradation, ubiquitination also modulates enzymatic activity. However, current mechanisms of ubiquitination-mediated enzymatic modulation are spatially constrained near enzyme–substrate interfaces. Here, we report a unique ubiquitination-mediated regulatory paradigm that activates the Polycomb repressive deubiquitinase (PR-DUB) complex from a site distal to the enzyme–substrate interface. We found that ASXL1 K351 monoubiquitination promotes nucleosomal H2AK119Ub deubiquitination by stabilizing the PR-DUB catalytic pocket, thereby increasing catalytic velocity (Vmax) without affecting substrate affinity (Km). Structurally, ubiquitin at ASXL1 K351 bridges the BAP1 and ASXL1 subunits, functioning as a cross-bracing ‘glue’ that constrains their conformational dynamics without altering the nucleosome-binding interface. Molecular dynamics and hydrogen–deuterium exchange mass spectrometry revealed that this modification locks PR-DUB in a catalytic state poised for substrate cleavage. This study reveals a unique ubiquitin function of intersubunit fastening through a molecular glue effect and clarifies the mechanism of PR-DUB activation.