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

Glycogen synthase kinase 3[beta] (GSK3[beta]) is a serine/threonine kinase involved in insulin, growth factor and Wnt signalling. In Wnt signalling, GSK3[beta] is recruited to a multiprotein complex via interaction with axin, where it hyperphosphorylates [beta]-catenin, marking it for ubiquitylation...

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Bibliographic Details
Published in:The EMBO journal 2003-02, Vol.22 (3), p.494
Main Authors: Dajani, Rana, Fraser, Elizabeth, S.Mark Roe, Yeo, Maggie, Good, Valerie M, Thompson, Vivienne, Dale, Trevor C, Pearl, Laurence H
Format: Article
Language:English
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Summary:Glycogen synthase kinase 3[beta] (GSK3[beta]) is a serine/threonine kinase involved in insulin, growth factor and Wnt signalling. In Wnt signalling, GSK3[beta] is recruited to a multiprotein complex via interaction with axin, where it hyperphosphorylates [beta]-catenin, marking it for ubiquitylation and destruction. We have now determined the crystal structure of GSK3[beta] in complex with a minimal GSK3[beta]-binding segment of axin, at 2.4 [Angstrom] resolution. The structure confirms the co-localization of the binding sites for axin and FRAT in the C-terminal domain of GSK3[beta], but reveals significant differences in the interactions made by axin and FRAT, mediated by conformational plasticity of the 285-299 loop in GSK3[beta]. Detailed comparison of the axin and FRAT GSK3[beta] complexes allows the generation of highly specific mutations, which abrogate binding of one or the other. Quantitative analysis suggests that the interaction of GSK3[beta] with the axin scaffold enhances phosphorylation of [beta]-catenin by >20 000-fold.
ISSN:0261-4189
1460-2075