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Structural insights into Ubr1-mediated N-degron polyubiquitination

Author

Listed:
  • Man Pan

    (The University of Chicago)

  • Qingyun Zheng

    (Tsinghua University
    Shanghai University)

  • Tian Wang

    (Tsinghua University)

  • Lujun Liang

    (Tsinghua University)

  • Junxiong Mao

    (Tsinghua University)

  • Chong Zuo

    (Tsinghua University)

  • Ruichao Ding

    (Tsinghua University)

  • Huasong Ai

    (Tsinghua University)

  • Yuan Xie

    (The University of Chicago)

  • Dong Si

    (University of Washington Bothell)

  • Yuanyuan Yu

    (The University of Chicago
    Shanghai University)

  • Lei Liu

    (Tsinghua University)

  • Minglei Zhao

    (The University of Chicago)

Abstract

The N-degron pathway targets proteins that bear a destabilizing residue at the N terminus for proteasome-dependent degradation1. In yeast, Ubr1—a single-subunit E3 ligase—is responsible for the Arg/N-degron pathway2. How Ubr1 mediates the initiation of ubiquitination and the elongation of the ubiquitin chain in a linkage-specific manner through a single E2 ubiquitin-conjugating enzyme (Ubc2) remains unknown. Here we developed chemical strategies to mimic the reaction intermediates of the first and second ubiquitin transfer steps, and determined the cryo-electron microscopy structures of Ubr1 in complex with Ubc2, ubiquitin and two N-degron peptides, representing the initiation and elongation steps of ubiquitination. Key structural elements, including a Ubc2-binding region and an acceptor ubiquitin-binding loop on Ubr1, were identified and characterized. These structures provide mechanistic insights into the initiation and elongation of ubiquitination catalysed by Ubr1.

Suggested Citation

  • Man Pan & Qingyun Zheng & Tian Wang & Lujun Liang & Junxiong Mao & Chong Zuo & Ruichao Ding & Huasong Ai & Yuan Xie & Dong Si & Yuanyuan Yu & Lei Liu & Minglei Zhao, 2021. "Structural insights into Ubr1-mediated N-degron polyubiquitination," Nature, Nature, vol. 600(7888), pages 334-338, December.
  • Handle: RePEc:nat:nature:v:600:y:2021:i:7888:d:10.1038_s41586-021-04097-8
    DOI: 10.1038/s41586-021-04097-8
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    Cited by:

    1. Yifei Zhou & Hongjun Li & Yi Huang & Jiahui Li & Guiyu Deng & Gong Chen & Zhen Xi & Chuanzheng Zhou, 2023. "Suppression of alpha-carbon racemization in peptide synthesis based on a thiol-labile amino protecting group," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Xiangwei Wu & Yunxiang Du & Lu-Jun Liang & Ruichao Ding & Tianyi Zhang & Hongyi Cai & Xiaolin Tian & Man Pan & Lei Liu, 2024. "Structure-guided engineering enables E3 ligase-free and versatile protein ubiquitination via UBE2E1," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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