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Structural basis of the recognition of the Dishevelled DEP domain in the Wnt signaling pathway

Nature Structural Biology volume 7, pages 1178–1184 (2000)Cite this article

Abstract

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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Figure 1: Structure-based amino acid sequence alignment of selected DEP domains.
Figure 2: Effect of Dvl C-terminal region on Lef-1 activation.
Figure 3: Solution structure of the DEP domain of mDvl1.
Figure 4: The hydrophobic core of the DEP domain.
Figure 5: Surface potential of the DEP domain.
Figure 6: Mutagenesis study of DvlC1.

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Acknowledgements

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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Authors and Affiliations

  1. Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Hing C. Wong, Jason T. Nguyen, Shamala Srinivas, Weixing Zhang & Jie Zheng

  2. Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, 06030, Connecticut, USA

    Junhao Mao, Bo Liu, Lin Li & Dianqing Wu

  3. Shanghai Institute of Biochemistry, Shanghai Institutes for Biological Sciences, The Chinese Academy of Sciences, Shanghai, China

    Lin Li

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Correspondence to Jie Zheng.

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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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