Structural basis of the Axin–adenomatous polyposis coli interaction

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Abstract
Axin and the adenomatous polyposis coli (APC) tumor suppressor protein are components of the Wnt/Wingless growth factor signaling pathway. In the absence of Wnt signal, Axin and APC regulate cytoplasmic levels of the proto‐oncogene β‐catenin through the formation of a large complex containing these three proteins, glycogen synthase kinase 3β (GSK3β) and several other proteins. Both Axin and APC are known to be critical for β‐catenin regulation, and truncations in APC that eliminate the Axin‐binding site result in human cancers. A protease‐resistant domain of Axin that contains the APC‐binding site is a member of the regulators of G‐protein signaling (RGS) superfamily. The crystal structures of this domain alone and in complex with an Axin‐binding sequence from APC reveal that the Axin–APC interaction occurs at a conserved groove on a face of the protein that is distinct from the G‐protein interface of classical RGS proteins. The molecular interactions observed in the Axin–APC complex provide a rationale for the evolutionary conservation seen in both proteins.