The Roles of Intrinsic Disorder in Orchestrating the Wnt-Pathway
The canonical Wnt-pathway plays a number of crucial roles in the development of organism. Malfunctions of this pathway lead to various diseases including cancer. In the inactivated state, this pathway involves five proteins, Axin, CKI-α, GSK-3β, APC, and β-catenin. We analyzed these proteins by a number of computational tools, such as PONDR®VLXT, PONDR®VSL2, MoRF-II predictor and Hydrophobic Cluster Analysis (HCA) to show that each of the Wnt-pathway proteins contains several intrinsically disordered regions. Based on a comprehensive analysis of published data we conclude that these disordered regions facilitate protein-protein interactions, post-translational modifications, and signaling. The scaffold protein Axin and another large protein, APC, act as flexible concentrators in gathering together all other proteins involved in the Wnt-pathway, emphasizing the role of intrinsically disordered regions in orchestrating the complex protein-protein interactions. We further explore the intricate roles of highly disordered APC in regulation of β-catenin function. Intrinsically disordered APC helps the collection of β-catenin from cytoplasm, facilitates the b-catenin delivery to the binding sites on Axin, and controls the final detachment of β-catenin from Axin.
Key words: Intrinsically disordered protein; Wnt-pathway; β-catenin; Axin; CKI-α ; GSK-3β ; APC; Signaling; Protein-protein interaction; Development.
This article can be cited as:
B. Xue, A.K. Dunker, V.N. Uversky The Roles of Intrinsic Disorder in Orchestrating the Wnt-Pathway J. Biomol Struct Dyn 29(5), 843-861 (2012).
1Department of Molecular Medicine, University of South Florida, Tampa,
FL 33612, USA