title: Large extent of disorder in Adenomatous Polyposis Coli offers a strategy to guard Wnt signalling against point mutations.
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.
authors.affiliation: Cellular Protein Chemistry, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands.
authors.forename: David P
authors.initials: DP
authors.lastname: Minde
authors.forename: Martina
authors.initials: M
authors.lastname: Radli
authors.forename: Federico
authors.initials: F
authors.lastname: Forneris
authors.forename: Madelon M
authors.initials: MM
authors.lastname: Maurice
authors.forename: Stefan G D
authors.initials: SG
authors.lastname: Rüdiger
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D006358:Hot Temperature; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D017354:Point Mutation; D017433:Protein Structure, Secondary; D058767:Protein Unfolding; D059748:Proteolysis; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins