The Wnt signaling pathway controls numerous cell fates in animal development and is also a major cancer pathway. Dishevelled (Dvl) transduces the Wnt signal by interacting with the cytoplasmic Axin complex. Dvl and Axin each contain a DIX domain whose molecular properties and structure are unknown. Here, we demonstrate that the DIX domain of Dvl2 mediates dynamic polymerization, which is essential for the signaling activity of Dvl2. The purified domain polymerizes gradually, reversibly and in a concentration dependent manner, ultimately forming fibrils. The Axin DIX domain has a novel structural fold largely composed of β-strands that engage in head-to-tail self-interaction to form filaments in the crystal. The DIX domain thus seems to mediate the formation of a dynamic interaction platform with a high local concentration of binding sites for transient Wnt signaling partners; this represents a previously uncharacterized mechanistic principle, signaling by reversible polymerization.
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We thank P. Evans, T. Crowther and S. Li for technical help and advice, M. Semenov (Harvard Medical School) for Dvl2 antiserum, C. Niehrs for discussion and communication of unpublished results, and H. Pelham, M. Goedert, B. Nichols, J. Murphy, R. Sear, Y. Tomimoto, H. Yamamoto, H. Komori, Y. Shomura, H. Axelrod and Y. Shiro for helpful discussions. This work was supported by a European Molecular Biology Organization long-term fellowship and a Marie-Curie postdoctoral fellowship (T.S.-R.); a Erwin-Schrödinger postdoctoral fellowship (M.F.); Grants-in-Aid for Young Scientists (B) (no. 17770093) from the Japan Society for Promotion of Science and the Ministry of Education, Culture, Sports, Science and Technology, Japan (N.S.); and the 21st COE Programs, the National Project on Protein Structural and Functional Analyses (Japan) and The Japanese Aerospace Exploration Agency Project (Y.H.).
The authors declare no competing financial interests.
Circular dichroism of wild-type and mutant DIX domains. (PDF 241 kb)
Additional sedimentation analysis of wild-type and mutant DIX domains. (PDF 88 kb)
The degree of Dvl2 oligomerization is not altered by Wnt signaling. (PDF 1777 kb)
The electron density peak at the molecular interface. (PDF 5687 kb)
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Schwarz-Romond, T., Fiedler, M., Shibata, N. et al. The DIX domain of Dishevelled confers Wnt signaling by dynamic polymerization. Nat Struct Mol Biol 14, 484–492 (2007) doi:10.1038/nsmb1247
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