Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction
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...
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doaj-909d22a097d24da0a1d1f2431d614ce42021-05-05T21:00:25ZengeLife Sciences Publications LtdeLife2050-084X2020-04-01910.7554/eLife.55015Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transductionWei Kan0https://orcid.org/0000-0002-6830-6714Michael D Enos1Elgin Korkmazhan2https://orcid.org/0000-0002-6872-9952Stefan Muennich3https://orcid.org/0000-0003-1355-737XDong-Hua Chen4Melissa V Gammons5Mansi Vasishtha6Mariann Bienz7https://orcid.org/0000-0002-7170-8706Alexander R Dunn8https://orcid.org/0000-0001-6096-4600Georgios Skiniotis9William I Weis10https://orcid.org/0000-0002-5583-6150Department of Structural Biology and Stanford University School of Medicine, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United StatesDepartment of Structural Biology and Stanford University School of Medicine, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United StatesDepartment of Chemical Engineering, Stanford University, Stanford, United States; Graduate Program in Biophysics, Stanford University, Stanford, United StatesDepartment of Structural Biology and Stanford University School of Medicine, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United StatesDepartment of Structural Biology and Stanford University School of Medicine, Stanford, United StatesMRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United KingdomDepartment of Structural Biology and Stanford University School of Medicine, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United StatesMRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United KingdomDepartment of Chemical Engineering, Stanford University, Stanford, United States; Graduate Program in Biophysics, Stanford University, Stanford, United StatesDepartment of Structural Biology and Stanford University School of Medicine, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United StatesDepartment of Structural Biology and Stanford University School of Medicine, Stanford, United States; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, United States; Graduate Program in Biophysics, Stanford University, Stanford, United StatesIn 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.https://elifesciences.org/articles/55015AxindishevelledDIX domainWnt signaling |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wei Kan Michael D Enos Elgin Korkmazhan Stefan Muennich Dong-Hua Chen Melissa V Gammons Mansi Vasishtha Mariann Bienz Alexander R Dunn Georgios Skiniotis William I Weis |
spellingShingle |
Wei Kan Michael D Enos Elgin Korkmazhan Stefan Muennich Dong-Hua Chen Melissa V Gammons Mansi Vasishtha Mariann Bienz Alexander R Dunn Georgios Skiniotis William I Weis Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction eLife Axin dishevelled DIX domain Wnt signaling |
author_facet |
Wei Kan Michael D Enos Elgin Korkmazhan Stefan Muennich Dong-Hua Chen Melissa V Gammons Mansi Vasishtha Mariann Bienz Alexander R Dunn Georgios Skiniotis William I Weis |
author_sort |
Wei Kan |
title |
Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction |
title_short |
Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction |
title_full |
Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction |
title_fullStr |
Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction |
title_full_unstemmed |
Limited dishevelled/Axin oligomerization determines efficiency of Wnt/β-catenin signal transduction |
title_sort |
limited dishevelled/axin oligomerization determines efficiency of wnt/β-catenin signal transduction |
publisher |
eLife Sciences Publications Ltd |
series |
eLife |
issn |
2050-084X |
publishDate |
2020-04-01 |
description |
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. |
topic |
Axin dishevelled DIX domain Wnt signaling |
url |
https://elifesciences.org/articles/55015 |
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