期刊
BIOCHEMISTRY
卷 50, 期 5, 页码 715-726出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi101236z
关键词
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资金
- Canadian Institutes of Health Research (CIHR) [74679]
- Canada Foundation for Innovation (CFI)
- Ontario Government
- Ontario Graduate Scholarship in Science and Technology (OGSST)
- Ontario Early Researcher Award
The Wnt/beta-catenin signaling pathway is critical to embryonic development as well as adult tissue regeneration. Dysregulation of this pathway can lead to a variety of human diseases, in particular cancers. Chibby (Cby), a small and highly conserved protein, plays an antagonistic role in Wnt signaling by inhibiting the binding of beta-catenin to Tcf/Lef family proteins, a protein interaction that is essential for the transcriptional activation of Wnt target genes. Cby is also involved in regulating intracellular distribution of beta-catenin. Phosphorylated Cby forms a ternary complex with 14-3-3 protein and beta-catenin, facilitating the export of beta-catenin from the nucleus. On the other hand, the antagonistic function of Cby is inhibited upon binding to thyroid cancer-1 (TC-1). To dissect the structure-function relationship of Cby, we have used NMR spectroscopy, ESI-MS, CD, and DLS to extensively characterize the structure of human Cby. Our results show that the 126-residue Cby is partially disordered under nondenaturing conditions. While the N-terminal portion of the protein is predominantly unstructured in solution, the C-terminal half of Cby adopts a coiled-coil structure through self-association. Initial data for the binding studies of Cby to 14-3-3 (one of the isoforms in the 14-3-3 family) and TC-1 via these two distinct structural modules have also been obtained. It is noteworthy that in a recent large-scale analysis of the intrinsically disordered proteome of mouse, a substantial number of disordered proteins are predicted to have coiled-coil motif presence in their sequences. The combination of these two molecular recognition features could facilitate disordered Cby in assembling protein complexes via different modes of interaction.
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