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Cullin–RING ubiquitin E3 ligase regulation by the COP9 signalosome

Author

Listed:
  • Simone Cavadini

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Eric S. Fischer

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel
    Dana-Farber Cancer Institute, LC-4312
    Harvard Medical School)

  • Richard D. Bunker

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Alessandro Potenza

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Gondichatnahalli M. Lingaraju

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Kenneth N. Goldie

    (Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel)

  • Weaam I. Mohamed

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Mahamadou Faty

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Georg Petzold

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Rohan E. J. Beckwith

    (Novartis Institutes for Biomedical Research)

  • Ritesh B. Tichkule

    (Novartis Institutes for Biomedical Research)

  • Ulrich Hassiepen

    (Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus)

  • Wassim Abdulrahman

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

  • Radosav S. Pantelic

    (Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel
    Gatan R&D, 5974 W)

  • Syota Matsumoto

    (Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University
    Graduate School of Science, Kobe University)

  • Kaoru Sugasawa

    (Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University
    Graduate School of Science, Kobe University)

  • Henning Stahlberg

    (Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel)

  • Nicolas H. Thomä

    (Friedrich Miescher Institute for Biomedical Research
    University of Basel)

Abstract

The cullin–RING ubiquitin E3 ligase (CRL) family comprises over 200 members in humans. The COP9 signalosome complex (CSN) regulates CRLs by removing their ubiquitin-like activator NEDD8. The CUL4A–RBX1–DDB1–DDB2 complex (CRL4ADDB2) monitors the genome for ultraviolet-light-induced DNA damage. CRL4ADBB2 is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4ADDB2 and the principles of CSN activation are poorly understood. Here we present cryo-electron microscopy structures for CSN in complex with neddylated CRL4A ligases to 6.4 Å resolution. The CSN conformers defined by cryo-electron microscopy and a novel apo-CSN crystal structure indicate an induced-fit mechanism that drives CSN activation by neddylated CRLs. We find that CSN and a substrate cannot bind simultaneously to CRL4A, favouring a deneddylated, inactive state for substrate-free CRL4 complexes. These architectural and regulatory principles appear conserved across CRL families, allowing global regulation by CSN.

Suggested Citation

  • Simone Cavadini & Eric S. Fischer & Richard D. Bunker & Alessandro Potenza & Gondichatnahalli M. Lingaraju & Kenneth N. Goldie & Weaam I. Mohamed & Mahamadou Faty & Georg Petzold & Rohan E. J. Beckwit, 2016. "Cullin–RING ubiquitin E3 ligase regulation by the COP9 signalosome," Nature, Nature, vol. 531(7596), pages 598-603, March.
    • Handle: RePEc:nat:nature:v:531:y:2016:i:7596:d:10.1038_nature17416
    DOI: 10.1038/nature17416
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    Cited by:

    1. Shuai Qiao & Chia-Wei Lee & Dawafuti Sherpa & Jakub Chrustowicz & Jingdong Cheng & Maximilian Duennebacke & Barbara Steigenberger & Ozge Karayel & Duc Tung Vu & Susanne Gronau & Matthias Mann & Floria, 2022. "Cryo-EM structures of Gid12-bound GID E3 reveal steric blockade as a mechanism inhibiting substrate ubiquitylation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Diana A. Llerena Schiffmacher & Shun-Hsiao Lee & Katarzyna W. Kliza & Arjan F. Theil & Masaki Akita & Angela Helfricht & Karel Bezstarosti & Camila Gonzalo-Hansen & Haico Attikum & Matty Verlaan-de Vr, 2024. "The small CRL4CSA ubiquitin ligase component DDA1 regulates transcription-coupled repair dynamics," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Xiang Huang & Xin Liu & Xingda Li & Yang Zhang & Jianjun Gao & Ying Yang & Yuan Jiang & Haiyu Gao & Chongsong Sun & Lina Xuan & Lexin Zhao & Jiahui Song & Hairong Bao & Zhiwen Zhou & Shangxuan Li & Xi, 2023. "Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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