Structural Characterization of Partially Disordered Human Chibby: Insights into Its Function in the Wnt-Signaling Pathway
Open Access
- 14 January 2011
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 50 (5), 715-726
- https://doi.org/10.1021/bi101236z
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.Keywords
This publication has 80 references indexed in Scilit:
- Linking folding and bindingCurrent Opinion in Structural Biology, 2009
- Large-Scale Analysis of Thermostable, Mammalian Proteins Provides Insights into the Intrinsically Disordered ProteomeJournal of Proteome Research, 2008
- Intrinsically Disordered Human C/EBP Homologous Protein Regulates Biological Activity of Colon Cancer Cells during Calcium StressJournal of Molecular Biology, 2008
- Structural basis for protein–protein interactions in the 14-3-3 protein familyProceedings of the National Academy of Sciences of the United States of America, 2006
- Exploiting heterogeneous sequence properties improves prediction of protein disorderProteins, 2005
- Coupled Folding and Binding with α-Helix-Forming Molecular Recognition ElementsBiochemistry, 2005
- Intrinsically unstructured proteins and their functionsNature Reviews Molecular Cell Biology, 2005
- WNT and β-catenin signalling: diseases and therapiesNature Reviews Genetics, 2004
- NMRPipe: A multidimensional spectral processing system based on UNIX pipesJournal of Biomolecular NMR, 1995
- Correlation of Backbone Amide and Aliphatic Side-Chain Resonances in 13C/15N-Enriched Proteins by Isotropic Mixing of 13C MagnetizationJournal of Magnetic Resonance, Series B, 1993