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

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.

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Publication Details

Journal
Nature Communications
Published
2025-10-15
DOI
https://doi.org/10.1038/s41467-025-64719-x
Citations
5
Primary Topic
Ubiquitin and proteasome pathways
Type
article
Field-Weighted Citation Impact
4.03
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article

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

Ming-Chieh Tsai, Ting Chen, Hsin-An Shih, Jessica Y. C. Huang et al.
5 citations
Nature Communications
Ubiquitin and proteasome pathways
4.03
article

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

Ming-Chieh Tsai, Ting Chen, Hsin-An Shih, Jessica Y. C. Huang, Yuan‐Chih Chang, Shang‐Te Danny Hsu, Steven Lin, Yong‐Sheng Wang, Piotr Drączkowski, Kuen‐Phon Wu, Shu‐Yu Lin, Szu-Ni Chen, Rosa Viner
article en
5 citations

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.

Nature CommunicationsVol. 16(1)
Medical University of Lublin (PL), National Taiwan University (TW), National Taipei University of Nursing and Health Science (TW), Genomics Research Center, Academia Sinica (TW), Institute of Biological Chemistry, Academia Sinica (TW), Institute of Sociology, Academia Sinica (TW), Hiroshima International University (JP), Thermo Fisher Scientific (United States) (US), Academia Sinica (TW)
Openalex Percentile: Top 6%
Ubiquitin and proteasome pathways
4.03
DOIOpen Access PDFOpenAlex
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