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

Author

Listed:
  • Piotr Draczkowski

    (Academia Sinica
    Medical University of Lublin)

  • Szu-Ni Chen

    (Academia Sinica)

  • Ting Chen

    (Academia Sinica)

  • Yong-Sheng Wang

    (Academia Sinica
    National Taiwan University)

  • Hsin-An Shih

    (Academia Sinica)

  • Jessica Y. C. Huang

    (Academia Sinica)

  • Ming-Chieh Tsai

    (Academia Sinica
    Academia Sinica)

  • Shu-Yu Lin

    (Academia Sinica
    Academia Sinica)

  • Steven Lin

    (Academia Sinica
    National Taiwan University)

  • Rosa Viner

    (Thermo Fisher Scientific)

  • Yuan-Chih Chang

    (Academia Sinica
    Academia Sinica)

  • Kuen-Phon Wu

    (Academia Sinica
    National Taiwan University)

  • Shang-Te Danny Hsu

    (Academia Sinica
    National Taiwan University
    Hiroshima University)

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.

Suggested Citation

  • 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 & Shang-Te , 2025. "Structural basis of K11/K48-branched ubiquitin chain recognition by the human 26S proteasome," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64719-x
    DOI: 10.1038/s41467-025-64719-x
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    References listed on IDEAS

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