Department 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
Michael D Enos
Department 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
Department of Chemical Engineering, Stanford University, Stanford, United States; Graduate Program in Biophysics, Stanford University, Stanford, United States
Department 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
Dong-Hua Chen
Department of Structural Biology and Stanford University School of Medicine, Stanford, United States
Melissa V Gammons
MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, United Kingdom
Mansi Vasishtha
Department 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
Department of Chemical Engineering, Stanford University, Stanford, United States; Graduate Program in Biophysics, Stanford University, Stanford, United States
Georgios Skiniotis
Department 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
Department 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 States
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.
