title: The roles of intrinsic disorder in orchestrating the Wnt-pathway.
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(r)VLXT, PONDR(r)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.
authors.affiliation: Department of Molecular Medicine, University of South Florida, Tampa, FL 33612, USA. vuversky@health.usf.edu
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.forename: A Keith
authors.initials: AK
authors.lastname: Dunker
authors.forename: Vladimir N
authors.initials: VN
authors.lastname: Uversky
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry* / Q000378:metabolism; D000595:Amino Acid Sequence; D060466:Axin Protein / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D048128:Casein Kinase Ialpha / Q000737:chemistry* / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011392:Proline; D054730:Protein Interaction Domains and Motifs; D017434:Protein Structure, Tertiary; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000737:chemistry* / Q000378:metabolism
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C495270:CTNNB1 protein, human; D051176:beta Catenin; D011392:Proline; D048128:Casein Kinase Ialpha; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3