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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).

Bin Xue1,2
A. Keith Dunker2
Vladimir N. Uversky1,3*

1Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA
2Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
3Institute for Biological Instrumentation, Russian Academy of Sciences, 142290 Pushchino, Moscow Region, Russia

vuversky@health.usf.edu

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