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<p>ZYG11B is a substrate receptor of the Cullin2-RING E3 ligase (CRL2), mediating the Gly/N-degron pathway and contributing to diverse processes including cell cycle control, protein homeostasis, apoptosis, and innate immunity. While previous studies resolved the structure of its truncated ARM domain, how full-length ZYG11B coordinates substrate engagement and CRL2<sup>ZYG11B</sup> assembly remains unclear. Here, we present cryo-EM structures of full-length human ZYG11B in complex with the EloB–EloC adaptor and a Gly/N-degron peptide, revealing a seahorse-like architecture with distinct interfaces for adaptor and substrate binding. Unexpectedly, ZYG11B adopts both monomeric and dimeric assemblies, with the dimer stabilizing two substrate-binding sites in opposite orientations. Functional assays demonstrate that interfaces mediating adaptor recruitment, substrate binding, and dimerization are essential for substrate degradation, suggesting a dynamic mechanism involving both assembly states. These findings provide a structural framework for understanding CRL2<sup>ZYG11B</sup>-mediated ubiquitination and offer mechanistic insights that may inform the rational design of ZYG11B-based applications.</p>

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Structures of ZYG11B-EloB-EloC-substrate complex reveal mechanisms of CRL2ZYG11B assembly and function

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月31日

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  • Ni Lin,
  • Han Feng,
  • Yushan Geng,
  • Yina Gao,
  • Miao Shi,
  • Songqing Liu,
  • Pu Gao,
  • Yong Wang

摘要

ZYG11B is a substrate receptor of the Cullin2-RING E3 ligase (CRL2), mediating the Gly/N-degron pathway and contributing to diverse processes including cell cycle control, protein homeostasis, apoptosis, and innate immunity. While previous studies resolved the structure of its truncated ARM domain, how full-length ZYG11B coordinates substrate engagement and CRL2ZYG11B assembly remains unclear. Here, we present cryo-EM structures of full-length human ZYG11B in complex with the EloB–EloC adaptor and a Gly/N-degron peptide, revealing a seahorse-like architecture with distinct interfaces for adaptor and substrate binding. Unexpectedly, ZYG11B adopts both monomeric and dimeric assemblies, with the dimer stabilizing two substrate-binding sites in opposite orientations. Functional assays demonstrate that interfaces mediating adaptor recruitment, substrate binding, and dimerization are essential for substrate degradation, suggesting a dynamic mechanism involving both assembly states. These findings provide a structural framework for understanding CRL2ZYG11B-mediated ubiquitination and offer mechanistic insights that may inform the rational design of ZYG11B-based applications.