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.
Highlights
The Wnt/b-catenin signaling pathway mediates cell fate specification during embryogenesis and tissue renewal in the adult (Nusse and Clevers, 2017)
In the absence of a Wnt signal, a cytosolic pool of b-catenin is bound in a ‘destruction complex’ that contains the scaffold protein Axin, the kinases GSK-3 and CK1, and the adenomatous polyposis coli protein (APC); phosphorylation of b-catenin leads to its ubiquitylation and destruction by the proteasome (Stamos and Weis, 2013)
The purified filaments run as a broad peak in size exclusion chromatography (SEC) with a size range of 4.9–9.5 MDa determined by Multi-Angle Light Scattering (MALS) (Figure 1b)
Summary
The Wnt/b-catenin signaling pathway mediates cell fate specification during embryogenesis and tissue renewal in the adult (Nusse and Clevers, 2017). In this pathway, secreted Wnt proteins activate growth control genes by stabilizing the transcriptional co-activator b-catenin. A current model for signal transduction is that ligand-bound Fzd recruits the cytosolic protein Dishevelled (Dvl), which binds to Axin and thereby recruits the destruction complex to the activated receptor complex.
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