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

Abstract
Data availability
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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

1. Kan W
2. Enos M
3. Muennich S
4. Skiniotis G
5. Weis WI
(2020) Dvl2 DIX filament coordinates
Protein Data Bank, 6VCC.

http://www.rcsb.org/6VCC
1. Kan W
2. Enos M
3. Muennich S
4. Skiniotis G
5. Weis WI
(2020) Dvl2 DIX filament cryo-EM map
EMBL-EBI, EMD-21148.

https://www.ebi.ac.uk/pdbe/emdb/EMD-21148

Article and author information

Author details

Wei Kan

Structural Biology and Molecular & Cellular Physiology, Stanford University, Stanford, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-6830-6714
Michael D Enos

Department of Structural Biology, Stanford University, Stanford, United States

Competing interests
No competing interests declared.
Elgin Korkmazhan

Chemical Engineering, Stanford University, Stanford, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-6872-9952
Stefan Muennich

Structural Biology and Molecular & Cellular Physiology, Stanford University, Stanford, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-1355-737X
Dong-Hua Chen

Structural Biology, Stanford University, Stanford, United States

Competing interests
No competing interests declared.
Melissa V Gammons

Protein and Nucleic Acid Chemistry, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom

Competing interests
No competing interests declared.
Mansi Vasishtha

Structural Biology and Molecular & Cellular Physiology, Stanford University, Stanford, United States

Competing interests
No competing interests declared.
Mariann Bienz

MRC Laboratory of Molecular Biology, Medical Research Council, Cambridge, United Kingdom

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-7170-8706
Alexander R Dunn

Department of Chemical Engineering, Stanford University, Stanford, United States

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-6096-4600
Georgios Skiniotis

Biological Chemistry, Stanford University, Ann Arbor, United States

Competing interests
No competing interests declared.
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.

"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.

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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.