Large extent of disorder in Adenomatous Polyposis Coli offers a strategy to guard Wnt signalling against point mutations

PLoS One. 2013 Oct 9;8(10):e77257. doi: 10.1371/journal.pone.0077257. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / genetics*
  • Adenomatous Polyposis Coli / metabolism
  • Adenomatous Polyposis Coli Protein / chemistry
  • Adenomatous Polyposis Coli Protein / genetics*
  • Adenomatous Polyposis Coli Protein / metabolism
  • Animals
  • Hot Temperature
  • Humans
  • Mutation
  • Phosphorylation
  • Point Mutation*
  • Protein Structure, Secondary
  • Protein Unfolding
  • Proteolysis
  • Signal Transduction
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*

Substances

  • Adenomatous Polyposis Coli Protein
  • Wnt Proteins

Grant support

SGDR was supported by the European Union's Sixth Framework Programme (FP6) by a Marie-Curie Excellence Grant (MEXT-CT-2005-025651) and by the Seventh Framework Programme (FP7) under grant agreement ManiFold n°317371, by a VIDI career development grant (700.55.421) by the Netherlands Organization for Scientific Research (NWO) and by a High Potential Grant of Utrecht University. MMM was supported by the European Research Council (ERC-StG no.242958) and by a High Potential Grant of Utrecht University. URLs of funders: NWO: http://www.nwo.nl/; EU: http://europa.eu/index_en.htm; Utrecht University: http://www.uu.nl/; ERC: http://erc.europa.eu/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.