Molecular mechanisms of beta-catenin recognition by adenomatous polyposis coli revealed by the structure of an APC-beta-catenin complex

The adenomatous polyposis coli (APC) tumor suppressor protein plays a criti cal role in regulating cellular levels of the oncogene product beta -cateni n. APC binds to beta -catenin through a series of homologous 15 and 20 amin o acid repeats. We have determined the crystal structure of a 15 amino acid beta -catenin binding repeat from APC bound to the armadillo repeat region of beta -catenin. Although it lacks significant sequence homology, the N-t erminal half of the repeat binds in a manner similar to portions of E-cadhe rin and XTcf3, but the remaining interactions are unique to APC. We discuss the implications of this new structure for the design of therapeutics, and present evidence from structural, biochemical and sequence data, which sug gest that the 20 amino acid repeats can adopt two modes of binding to beta -catenin.