Large Extent of Disorder in Adenomatous Polyposis Coli Offers a Strategy to Guard Wnt Signalling against Point Mutations
Publication date
2013-10-09
Authors
Minde, David P.
Radli, Martina
Forneris, Federico
Maurice, Madelon M.
Rüdiger, S.G.D.
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Document Type
Article
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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. © 2013 Minde et al.
Keywords
creatine kinase BB, creatine kinase BB epsilon, unclassified drug, alpha helix, article, Caenorhabditis elegans, colon polyposis, conformational transition, controlled study, disease activity, gel permeation chromatography, gene cluster, gene structure, genetic susceptibility, human, human tissue, in vitro study, missense mutation, mutational analysis, nonhuman, point mutation, protein degradation, protein phosphorylation, protein secondary structure, protein structure, protein unfolding, regulatory mechanism, structure analysis, Wnt signaling pathway, SDG 3 - Good Health and Well-being
Citation
Minde, D P, Radli, M, Forneris, F, Maurice, M M & Rüdiger, S G D 2013, 'Large Extent of Disorder in Adenomatous Polyposis Coli Offers a Strategy to Guard Wnt Signalling against Point Mutations', PLoS One, vol. 8, no. 10, e77257. https://doi.org/10.1371/journal.pone.0077257