The roles of intrinsic disorder in orchestrating the wnt-pathway

Bin Xue, A. Keith Dunker, Vladimir N. Uversky

Research output: Contribution to journalArticle

31 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)843-861
Number of pages19
JournalJournal of Biomolecular Structure and Dynamics
Volume29
Issue number5
DOIs
StatePublished - Apr 2012

Keywords

  • β-catenin
  • APC
  • Axin
  • CKI-α
  • Development
  • GSK-3β
  • Intrinsically disordered protein
  • Protein-protein interaction
  • Signaling
  • Wnt-pathway

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

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