A direct heterotypic interaction between theDIXdomains ofDishevelled and Axin mediates signalingto -catenin

摘要

The Wnt–-catenin signaling pathway regulates embryonic development and tissue homeostasis throughout theanimal kingdom. Signaling through this pathway crucially depends on the opposing activities of two cytoplasmicmultiprotein complexes: the Axin destruction complex, which destabilizes the downstream effector -catenin,and the Dishevelled signalosome, which inactivates the Axin complex and thus enables -catenin to accumulateand operate a transcriptional switch in the nucleus. These complexes are assembled by dynamic head-to-tailpolymerization of the DIX domains of Axin or Dishevelled, respectively, which increases their avidity for signalingeffectors. Axin also binds to Dishevelled through its DIX domain. Here, we report the crystal structure of the heterodimericcomplex between the two DIX domains of Axin and Dishevelled. This heterotypic interface resembles theinterfaces observed in the individual homopolymers, albeit exhibiting a slight rearrangement of electrostaticinteractions and hydrogen bonds, consistent with the heterotypic interaction being favored over the homotypicAxin DIX interaction. Last, cell-based signaling assays showed that heterologous polymerizing domains functionallysubstituted for the DIX domain of Dishevelled provided that these Dishevelled chimeras retained a DIX head ortail surface capable of binding to Axin. These findings indicate that the interaction between Dishevelled and Axinthrough their DIX domains is crucial for signaling to -catenin.