Structural basis for recruitment of glycogen synthase kinase 3β to the axin-APC scaffold complex

Glycogen synthase kinase 3β (GSK3β) is a serine/threonine kinase involved in insulin, growth factor and Wnt signalling. In Wnt signalling, GSK3β is recruited to a multiprotein complex via interaction with axin, where it hyperphosphorylates β‐catenin, marking it for ubiquitylation and destruction. We have now determined the crystal structure of GSK3β in complex with a minimal GSK3β‐binding segment of axin, at 2.4 Å resolution. The structure confirms the co‐localization of the binding sites for axin and FRAT in the C‐terminal domain of GSK3β, but reveals significant differences in the interactions made by axin and FRAT, mediated by conformational plasticity of the 285—299 loop in GSK3β. Detailed comparison of the axin and FRAT GSK3β complexes allows the generation of highly specific mutations, which abrogate binding of one or the other. Quantitative analysis suggests that the interaction of GSK3β with the axin scaffold enhances phosphorylation of β‐catenin by >20 000‐fold.