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Ubiquitination of the Dishevelled DIX domain blocks its head-to-tail polymerization

Author

Listed:
  • Julia Madrzak

    (MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue)

  • Marc Fiedler

    (MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue)

  • Christopher M. Johnson

    (MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue)

  • Richard Ewan

    (MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee)

  • Axel Knebel

    (MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee)

  • Mariann Bienz

    (MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue)

  • Jason W. Chin

    (MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue)

Abstract

Dishevelled relays Wnt signals from the plasma membrane to different cytoplasmic effectors. Its signalling activity depends on its DIX domain, which undergoes head-to-tail polymerization to assemble signalosomes. The DIX domain is ubiquitinated in vivo at multiple lysines, which can be antagonized by various deubiquitinases (DUBs) including the CYLD tumour suppressor that attenuates Wnt signalling. Here, we generate milligram quantities of pure human Dvl2 DIX domain mono-ubiquitinated at two lysines (K54 and K58) by genetically encoded orthogonal protection with activated ligation (GOPAL), to investigate their effect on DIX polymerization. We show that the ubiquitination of DIX at K54 blocks its polymerization in solution, whereas DIX58-Ub remains oligomerization-competent. DUB profiling identified 28 DUBs that cleave DIX-ubiquitin conjugates, half of which prefer, or are specific for, DIX54-Ub, including Cezanne and CYLD. These DUBs thus have the potential to promote Dvl polymerization and signalosome formation, rather than antagonize it as previously thought for CYLD.

Suggested Citation

  • Julia Madrzak & Marc Fiedler & Christopher M. Johnson & Richard Ewan & Axel Knebel & Mariann Bienz & Jason W. Chin, 2015. "Ubiquitination of the Dishevelled DIX domain blocks its head-to-tail polymerization," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7718
    DOI: 10.1038/ncomms7718
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    Cited by:

    1. Victoria H. Ng & Zachary Spencer & Leif R. Neitzel & Anmada Nayak & Matthew A. Loberg & Chen Shen & Sara N. Kassel & Heather K. Kroh & Zhenyi An & Christin C. Anthony & Jamal M. Bryant & Amanda Lawson, 2023. "The USP46 complex deubiquitylates LRP6 to promote Wnt/β-catenin signaling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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