1. Structural Biology and Molecular Biophysics

Limited Dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction

  1. Wei Kan
  2. Michael D Enos
  3. Elgin Korkmazhan
  4. Stefan Muennich
  5. Dong-Hua Chen
  6. Melissa V Gammons
  7. Mansi Vasishtha
  8. Mariann Bienz
  9. Alexander R Dunn
  10. Georgios Skiniotis
  11. William I Weis  Is a corresponding author
  1. Stanford University, United States
  2. MRC Laboratory of Molecular Biology, United Kingdom
  3. Medical Research Council, United Kingdom
  4. Stanford University School of Medicine, United States
https://doi.org/10.7554/eLife.55015
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Cite this article
  1. Wei Kan
  2. Michael D Enos
  3. Elgin Korkmazhan
  4. Stefan Muennich
  5. Dong-Hua Chen
  6. Melissa V Gammons
  7. Mansi Vasishtha
  8. Mariann Bienz
  9. Alexander R Dunn
  10. Georgios Skiniotis
  11. William I Weis
(2020)
Limited Dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction
eLife 9:e55015.
https://doi.org/10.7554/eLife.55015
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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

The following data sets were generated

Article and author information

Author details

  1. Wei Kan

    Structural Biology and Molecular & Cellular Physiology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6830-6714

  2. Michael D Enos

    Department of Structural Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  3. Elgin Korkmazhan

    Chemical Engineering, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6872-9952

  4. Stefan Muennich

    Structural Biology and Molecular & Cellular Physiology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1355-737X

  5. Dong-Hua Chen

    Structural Biology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  6. Melissa V Gammons

    Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.

  7. Mansi Vasishtha

    Structural Biology and Molecular & Cellular Physiology, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.

  8. Mariann Bienz

    MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7170-8706

  9. Alexander R Dunn

    Department of Chemical Engineering, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6096-4600

  10. Georgios Skiniotis

    Biological Chemistry, Stanford University, Ann Arbor, United States
    Competing interests
    No competing interests declared.

  11. William I Weis

    Departments of Structural Biology and of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States
    For correspondence
    weis@stanford.edu
    Competing interests
    William I Weis, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5583-6150

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

  1. Mingjie Zhang, Hong Kong University of Science and Technology, Hong Kong

Version history

  1. Received: January 9, 2020
  2. Accepted: April 15, 2020
  3. Accepted Manuscript published: April 16, 2020 (version 1)
  4. 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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  1. Wei Kan
  2. Michael D Enos
  3. Elgin Korkmazhan
  4. Stefan Muennich
  5. Dong-Hua Chen
  6. Melissa V Gammons
  7. Mansi Vasishtha
  8. Mariann Bienz
  9. Alexander R Dunn
  10. Georgios Skiniotis
  11. William I Weis
(2020)
Limited Dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction
eLife 9:e55015.
https://doi.org/10.7554/eLife.55015

Share this article

https://doi.org/10.7554/eLife.55015

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