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Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome

Author

Listed:
  • Sarah V. Faull

    (The Institute of Cancer Research)

  • Andy M. C. Lau

    (King’s College London)

  • Chloe Martens

    (King’s College London)

  • Zainab Ahdash

    (King’s College London)

  • Kjetil Hansen

    (King’s College London)

  • Hugo Yebenes

    (The Institute of Cancer Research
    Consejo Superior de Investigaciones Científicas)

  • Carla Schmidt

    (Martin Luther University Halle-Wittenberg, Kurt-Mothes-Strasse 3a)

  • Fabienne Beuron

    (The Institute of Cancer Research)

  • Nora B. Cronin

    (The Institute of Cancer Research)

  • Edward P. Morris

    (The Institute of Cancer Research)

  • Argyris Politis

    (King’s College London)

Abstract

Cullin-Ring E3 Ligases (CRLs) regulate a multitude of cellular pathways through specific substrate receptors. The COP9 signalosome (CSN) deactivates CRLs by removing NEDD8 from activated Cullins. Here we present structures of the neddylated and deneddylated CSN-CRL2 complexes by combining single-particle cryo-electron microscopy (cryo-EM) with chemical cross-linking mass spectrometry (XL-MS). These structures suggest a conserved mechanism of CSN activation, consisting of conformational clamping of the CRL2 substrate by CSN2/CSN4, release of the catalytic CSN5/CSN6 heterodimer and finally activation of the CSN5 deneddylation machinery. Using hydrogen-deuterium exchange (HDX)-MS we show that CRL2 activates CSN5/CSN6 in a neddylation-independent manner. The presence of NEDD8 is required to activate the CSN5 active site. Overall, by synergising cryo-EM with MS, we identify sensory regions of the CSN that mediate its stepwise activation and provide a framework for understanding the regulatory mechanism of other Cullin family members.

Suggested Citation

  • Sarah V. Faull & Andy M. C. Lau & Chloe Martens & Zainab Ahdash & Kjetil Hansen & Hugo Yebenes & Carla Schmidt & Fabienne Beuron & Nora B. Cronin & Edward P. Morris & Argyris Politis, 2019. "Structural basis of Cullin 2 RING E3 ligase regulation by the COP9 signalosome," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11772-y
    DOI: 10.1038/s41467-019-11772-y
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    Cited by:

    1. Zhong Guo & Rinky D. Parakra & Ying Xiong & Wayne A. Johnston & Patricia Walden & Selvakumar Edwardraja & Shayli Varasteh Moradi & Jacobus P. J. Ungerer & Hui-wang Ai & Jonathan J. Phillips & Kirill A, 2022. "Engineering and exploiting synthetic allostery of NanoLuc luciferase," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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