Large Extent of Disorder in Adenomatous Polyposis Coli Offers a Strategy to Guard Wnt Signalling against Point Mutations
Open Access
- 9 October 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (10), e77257
- https://doi.org/10.1371/journal.pone.0077257
Abstract
Mutations in the central region of the signalling hub Adenomatous Polyposis Coli (APC) cause colorectal tumourigenesis. The structure of this region remained unknown. Here, we characterise the Mutation Cluster Region in APC (APC-MCR) as intrinsically disordered and propose a model how this structural feature may contribute to regulation of Wnt signalling by phosphorylation. APC-MCR was susceptible to proteolysis, lacked α-helical secondary structure and did not display thermal unfolding transition. It displayed an extended conformation in size exclusion chromatography and was accessible for phosphorylation by CK1ε in vitro. The length of disordered regions in APC increases with species complexity, from C. elegans to H. sapiens. We speculate that the large disordered region harbouring phosphorylation sites could be a successful strategy to stabilise tight regulation of Wnt signalling against single missense mutations.Keywords
This publication has 70 references indexed in Scilit:
- Triple SILAC to Determine Stimulus Specific Interactions in the Wnt PathwayJournal of Proteome Research, 2011
- Structural basis for the recognition of Asef by adenomatous polyposis coliCell Research, 2011
- Protein disorder—a breakthrough invention of evolution?Current Opinion in Structural Biology, 2011
- Residue-Specific Side-Chain Packing Determines the Backbone Dynamics of Transmembrane Model HelicesBiophysical Journal, 2010
- Sequence Determinants of Compaction in Intrinsically Disordered ProteinsBiophysical Journal, 2010
- Understanding protein non-foldingBiochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2010
- PONDR-FIT: A meta-predictor of intrinsically disordered amino acidsBiochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2010
- Intrinsic disorder in scaffold proteins: Getting more from lessProgress in Biophysics and Molecular Biology, 2008
- Intrinsically Disordered Proteins in Human Diseases: Introducing the D2ConceptAnnual Review of Biophysics, 2008
- Crystal structure of the amino-terminal coiled-coil domain of the APC tumor suppressor 1 1Edited by I. A. WilsonJournal of Molecular Biology, 2000