The DEP domain of Dishevelled (Dvl) proteins transduces signals to effector proteins downstream of Dvl in the Wnt pathway. Here we report that DEP-containing mutants inhibit Wnt-induced, but not Dvl-induced, activation of the transcription factor Lef-1. This inhibitory effect is weakened by a K434M mutation. Nuclear magnetic resonance spectroscopy revealed that the DEP domain of mouse Dvl1 comprises a three-helix bundle, a β-hairpin `arm' and two short β-strands at the C-terminal region. Lys 434 is located at the tip of the β-hairpin `arm'. Based on our findings, we conclude that DEP interacts with regulators upstream of Dvl via a strong electric dipole on the molecule's surface created by Lys 434, Asp 445 and Asp 448; the electric dipole and the putative membrane binding site are at two different locations.
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This work was funded by the American Lebanese Syrian Associated Charities to, by a Cancer Center (CORE) support grant from the National Cancer Institute and by a research grant from the National Institute of General Medical Science. We thank S. White and D. Cowburn for critical reading and comments on the manuscript; P. Mehta for help with data base searching and protein sequence analysis; J. Cay Jones, A. McArthur, C. Ross, and F. Witte for scientific editing. J.T.N is a trainee of the professional oncology program (POE) at St. Jude, and was funded by the National Cancer Institute and American Lebanese Syrian Associated Charities.
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Wong, H., Mao, J., Nguyen, J. et al. Structural basis of the recognition of the Dishevelled DEP domain in the Wnt signaling pathway. Nat Struct Mol Biol 7, 1178–1184 (2000). https://doi.org/10.1038/82047
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