The Roles of Intrinsic Disorder in Orchestrating the Wnt-Pathway |
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Authors: | Bin Xue A Keith Dunker Vladimir N Uversky |
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Institution: | 1. Department of Molecular Medicine , University of South Florida , Tampa , FL , 33612 , USA;2. Center for Computational Biology and Bioinformatics , Indiana University School of Medicine , Indianapolis , IN , 46202 , USA;3. Center for Computational Biology and Bioinformatics , Indiana University School of Medicine , Indianapolis , IN , 46202 , USA;4. Institute for Biological Instrumentation, Russian Academy of Sciences , 142290 , Pushchino , Moscow Region , Russia |
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Abstract: | Abstract 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 β-catenin delivery to the binding sites on Axin, and controls the final detachment of β-catenin from Axin. |
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Keywords: | Intrinsically disordered protein Wnt-pathway β-catenin Axin CKI-α GSK-3β APC Signaling Protein-protein interaction Development |
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