title: Structural characterization of partially disordered human Chibby: insights into its function in the Wnt-signaling pathway.
abstract: The Wnt/β-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 β-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 β-catenin. Phosphorylated Cby forms a ternary complex with 14-3-3 protein and β-catenin, facilitating the export of β-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 14-3-3ζ (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.
authors.affiliation: Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Sulayman
authors.initials: S
authors.lastname: Mokhtarzada
authors.forename: Corey
authors.initials: C
authors.lastname: Yu
authors.forename: Anne
authors.initials: A
authors.lastname: Brickenden
authors.forename: Wing-Yiu
authors.initials: WY
authors.lastname: Choy
mesh_terms: D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C473750:CBY1 protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D051153:Wnt Proteins