The third 20 amino acid repeat is the tightest binding site of APC for beta-catenin

J Mol Biol. 2006 Jun 30;360(1):133-44. doi: 10.1016/j.jmb.2006.04.064. Epub 2006 May 15.


Adenomatous polyposis coli (APC) plays a critical role in the Wnt signaling pathway by tightly regulating beta-catenin turnover and localization. The central region of APC is responsible for APC-beta-catenin interactions through its seven 20 amino acid (20aa) repeats and three 15 amino acid (15aa) repeats. Using isothermal titration calorimetry, we have determined the binding affinities of beta-catenin with an APC 15aa repeat fragment and each of the seven 20aa repeats in both phosphorylated and unphosphorylated states. Despite sequence homology, different beta-catenin binding repeats of APC have dramatically different binding affinities with beta-catenin and thus may play different biological roles. The third 20aa repeat is by far the tightest binding site for beta-catenin among all the repeats. The fact that most APC mutations associated with colon cancers have lost the third 20aa repeat underlines the importance of APC-beta-catenin interaction in Wnt signaling and human diseases. For every 20aa repeat, phosphorylation dramatically increases its binding affinity for beta-catenin, suggesting phosphorylation has a critical regulatory role in APC function. In addition, our CD and NMR studies demonstrate that the central region of APC is unstructured in the absence of beta-catenin and Axin, and suggest that beta-catenin may interact with each of the APC 15aa and 20aa repeats independently.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli / metabolism*
  • Amino Acid Sequence
  • Binding Sites
  • DNA Mutational Analysis
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Signal Transduction
  • Thermodynamics
  • beta Catenin / chemistry*
  • beta Catenin / metabolism


  • beta Catenin