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

Xiangwei Wu, Huasong Ai, Junxiong Mao, Hongyi Cai, Lu-Jun Liang, Zebin Tong, Zhiheng Deng, Qingyun Zheng (), Lei Liu () and Man Pan ()
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Xiangwei Wu: Shanghai Jiao Tong 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

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59569-6

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