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Structural visualization of HECT-type E3 ligase Ufd4 accepting and transferring ubiquitin to form K29/K48-branched polyubiquitination

Author

Listed:
  • Xiangwei Wu

    (Shanghai Jiao Tong University
    Tsinghua University)

  • Huasong Ai

    (Shanghai Jiao Tong University)

  • Junxiong Mao

    (Tsinghua University)

  • Hongyi Cai

    (Tsinghua University)

  • Lu-Jun Liang

    (Tsinghua University)

  • Zebin Tong

    (Tsinghua University)

  • Zhiheng Deng

    (Tsinghua University)

  • Qingyun Zheng

    (Shanghai Jiao Tong University)

  • Lei Liu

    (Tsinghua University)

  • Man Pan

    (Shanghai Jiao Tong University
    Zhengzhou)

Abstract

The K29/K48-linked ubiquitination generated by the cooperative catalysis of E3 ligase Ufd4 and Ubr1 is an enhanced protein degradation signal, in which Ufd4 is responsible for introducing K29-linked ubiquitination to K48-linked ubiquitin chains to augment polyubiquitination. How HECT-E3 ligase Ufd4 mediates the ubiquitination event remains unclear. Here, we biochemically determine that Ufd4 preferentially catalyses K29-linked ubiquitination on K48-linked ubiquitin chains to generate K29/K48-branched ubiquitin chains and capture structural snapshots of Ub transfer cascades for Ufd4-mediated ubiquitination. The N-terminal ARM region and HECT domain C-lobe of Ufd4 are identified and characterized as key structural elements that together recruit K48-linked diUb and orient Lys29 of its proximal Ub to the active cysteine of Ufd4 for K29-linked branched ubiquitination. These structures not only provide mechanistic insights into the architecture of the Ufd4 complex but also provide structural visualization of branched ubiquitin chain formation by a HECT-type E3 ligase.

Suggested Citation

  • Xiangwei Wu & Huasong Ai & Junxiong Mao & Hongyi Cai & Lu-Jun Liang & Zebin Tong & Zhiheng Deng & Qingyun Zheng & Lei Liu & Man Pan, 2025. "Structural visualization of HECT-type E3 ligase Ufd4 accepting and transferring ubiquitin to form K29/K48-branched polyubiquitination," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59569-6
    DOI: 10.1038/s41467-025-59569-6
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