Limited Dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction
- Stanford University, United States
- MRC Laboratory of Molecular Biology, United Kingdom
- Medical Research Council, United Kingdom
- Stanford University School of Medicine, United States
Abstract
In Wnt/β-catenin signaling, the transcriptional coactivator β-catenin is regulated by its phosphorylation in a complex that includes the scaffold protein Axin and associated kinases. Wnt binding to its coreceptors activates the cytosolic effector Dishevelled (Dvl), leading to the recruitment of Axin and the inhibition of β-catenin phosphorylation. This process requires interaction of homologous DIX domains present in Dvl and Axin, but is mechanistically undefined. We show that Dvl DIX forms antiparallel, double-stranded oligomers in vitro, and that Dvl in cells forms oligomers typically <10 molecules at endogenous expression levels. Axin DIX (DAX) forms small single-stranded oligomers, but its self-association is stronger than that of DIX. DAX caps the ends of DIX oligomers, such that a DIX oligomer has at most four DAX binding sites. The relative affinities and stoichiometry of the DIX-DAX interaction provide a mechanism for efficient inhibition of β-catenin phosphorylation upon Axin recruitment to the Wnt receptor complex.
Data availability
Coordinates of the Dvl2 DIX filament have been deposited in the PDB, code 6VCC, and the cryo-EM map in the EMDB, code EMD-21148
Article and author information
Author details
Funding
National Institute of General Medical Sciences (GM119156)
- William I Weis
National Institute of General Medical Sciences (GM130332)
- Alexander R Dunn
National Institute of General Medical Sciences (T32 GM007276)
- Michael D Enos
Pew Charitable Trusts (Pew Scholars Innovation Award 00031375)
- Georgios Skiniotis
- William I Weis
Stanford Bio-X Graduate Fellowship (Graduate fellowship)
- Elgin Korkmazhan
Fritz Thyssen Foundation (Postdoctoral Fellowship)
- Stefan Muennich
HHMI Faculty Scholar (N/A)
- Alexander R Dunn
Medical Research Council (MC_U105192713)
- Mariann Bienz
Cancer Research UK (C7379/A15291)
- Mariann Bienz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mingjie Zhang, Hong Kong University of Science and Technology, Hong Kong
Publication history
- Received: January 9, 2020
- Accepted: April 15, 2020
- Accepted Manuscript published: April 16, 2020 (version 1)
- Version of Record published: May 5, 2020 (version 2)
Copyright
© 2020, Kan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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