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

Julia Madrzak, Marc Fiedler, Christopher M. Johnson, Richard Ewan, Axel Knebel, Mariann Bienz (Lead / Corresponding author), Jason W. Chin (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    49 Citations (Scopus)


    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.

    Original languageEnglish
    Article number6718
    Number of pages11
    JournalNature Communications
    Publication statusPublished - 24 Apr 2015

    ASJC Scopus subject areas

    • General Biochemistry,Genetics and Molecular Biology
    • General Chemistry
    • General Physics and Astronomy


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