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Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly

Author

Listed:
  • Daniel Horn-Ghetko

    (Max Planck Institute of Biochemistry)

  • David T. Krist

    (Max Planck Institute of Biochemistry
    Carle Illinois College of Medicine)

  • J. Rajan Prabu

    (Max Planck Institute of Biochemistry)

  • Kheewoong Baek

    (Max Planck Institute of Biochemistry)

  • Monique P. C. Mulder

    (Leiden University Medical Centre)

  • Maren Klügel

    (Max Planck Institute of Biochemistry)

  • Daniel C. Scott

    (St Jude Children’s Research Hospital)

  • Huib Ovaa

    (Leiden University Medical Centre)

  • Gary Kleiger

    (University of Nevada, Las Vegas)

  • Brenda A. Schulman

    (Max Planck Institute of Biochemistry
    St Jude Children’s Research Hospital)

Abstract

E3 ligases are typically classified by hallmark domains such as RING and RBR, which are thought to specify unique catalytic mechanisms of ubiquitin transfer to recruited substrates1,2. However, rather than functioning individually, many neddylated cullin–RING E3 ligases (CRLs) and RBR-type E3 ligases in the ARIH family—which together account for nearly half of all ubiquitin ligases in humans—form E3–E3 super-assemblies3–7. Here, by studying CRLs in the SKP1–CUL1–F-box (SCF) family, we show how neddylated SCF ligases and ARIH1 (an RBR-type E3 ligase) co-evolved to ubiquitylate diverse substrates presented on various F-box proteins. We developed activity-based chemical probes that enabled cryo-electron microscopy visualization of steps in E3–E3 ubiquitylation, initiating with ubiquitin linked to the E2 enzyme UBE2L3, then transferred to the catalytic cysteine of ARIH1, and culminating in ubiquitin linkage to a substrate bound to the SCF E3 ligase. The E3–E3 mechanism places the ubiquitin-linked active site of ARIH1 adjacent to substrates bound to F-box proteins (for example, substrates with folded structures or limited length) that are incompatible with previously described conventional RING E3-only mechanisms. The versatile E3–E3 super-assembly may therefore underlie widespread ubiquitylation.

Suggested Citation

  • Daniel Horn-Ghetko & David T. Krist & J. Rajan Prabu & Kheewoong Baek & Monique P. C. Mulder & Maren Klügel & Daniel C. Scott & Huib Ovaa & Gary Kleiger & Brenda A. Schulman, 2021. "Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly," Nature, Nature, vol. 590(7847), pages 671-676, February.
  • Handle: RePEc:nat:nature:v:590:y:2021:i:7847:d:10.1038_s41586-021-03197-9
    DOI: 10.1038/s41586-021-03197-9
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    Citations

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    Cited by:

    1. Xiangyi S. Wang & Thomas R. Cotton & Sarah J. Trevelyan & Lachlan W. Richardson & Wei Ting Lee & John Silke & Bernhard C. Lechtenberg, 2023. "The unifying catalytic mechanism of the RING-between-RING E3 ubiquitin ligase family," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Tian-Chen Xiong & Ming-Cong Wei & Fang-Xu Li & Miao Shi & Hu Gan & Zhen Tang & Hong-Peng Dong & Tianzi Liuyu & Pu Gao & Bo Zhong & Zhi-Dong Zhang & Dandan Lin, 2022. "The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Daniel C. Scott & Suresh Dharuman & Elizabeth Griffith & Sergio C. Chai & Jarrid Ronnebaum & Moeko T. King & Rajendra Tangallapally & Chan Lee & Clifford T. Gee & Lei Yang & Yong Li & Victoria C. Loud, 2024. "Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Xiangwei Wu & Yunxiang Du & Lu-Jun Liang & Ruichao Ding & Tianyi Zhang & Hongyi Cai & Xiaolin Tian & Man Pan & Lei Liu, 2024. "Structure-guided engineering enables E3 ligase-free and versatile protein ubiquitination via UBE2E1," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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