Structural basis of K11/K48-branched ubiquitin chain recognition by the human 26S proteasome

Piotr Draczkowski, Szu-Ni Chen, Ting Chen, Yong-Sheng Wang, Hsin-An Shih, Jessica Y. C. Huang, Ming-Chieh Tsai, Shu-Yu Lin, Steven Lin, Rosa Viner, Yuan-Chih Chang, Kuen-Phon Wu and Shang-Te Danny Hsu ()
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Piotr Draczkowski: Academia Sinica
Szu-Ni Chen: Academia Sinica
Ting Chen: Academia Sinica
Yong-Sheng Wang: Academia Sinica
Hsin-An Shih: Academia Sinica
Jessica Y. C. Huang: Academia Sinica
Ming-Chieh Tsai: Academia Sinica
Shu-Yu Lin: Academia Sinica
Steven Lin: Academia Sinica
Rosa Viner: Thermo Fisher Scientific
Yuan-Chih Chang: Academia Sinica
Kuen-Phon Wu: Academia Sinica
Shang-Te Danny Hsu: Academia Sinica

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

Abstract: Abstract Beyond the canonical K48-linked homotypic polyubiquitination for proteasome-targeted proteolysis, K11/K48-branched ubiquitin (Ub) chains are involved in fast-tracking protein turnover during cell cycle progression and proteotoxic stress. Here, we report cryo-EM structures of human 26S proteasome in a complex with a K11/K48-branched Ub chain. The structures revealed a multivalent substrate recognition mechanism involving a hitherto unknown K11-linked Ub binding site at the groove formed by RPN2 and RPN10 in addition to the canonical K48-linkage binding site formed by RPN10 and RPT4/5 coiled-coil. Additionally, RPN2 recognizes an alternating K11-K48-linkage through a conserved motif similar to the K48-specific T1 binding site of RPN1. The insights gleaned from these structures explain the molecular mechanism underlying the recognition of the K11/K48-branched Ub as a priority signal in the ubiquitin-mediated proteasomal degradation.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64719-x

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DOI: 10.1038/s41467-025-64719-x

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