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Wnt signalosome assembly is governed by conformational flexibility of Axin and by the AP2 clathrin adaptor
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Wnt signalosome assembly is governed by conformational flexibility of Axin and by the AP2 clathrin adaptor
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Wnt signalosome assembly is governed by conformational flexibility of Axin and by the AP2 clathrin adaptor
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Journal Article
Wnt signalosome assembly is governed by conformational flexibility of Axin and by the AP2 clathrin adaptor
2025
Overview
Wnt signal transduction relies on the direct inhibition of GSK3 by phosphorylated PPPSPxS motifs within the cytoplasmic tail of the LRP6 co-receptor. How GSK3 is recruited to LRP6 remains unclear. Here, we use nuclear magnetic resonance spectroscopy to identify the membrane-proximal PPPSPxS motif and its flanking sequences as the primary binding site for both Axin and GSK3, and an intrinsically disordered segment of Axin as its LRP6-interacting region (LIR). Co-immunoprecipitation and CRISPR-engineered mutations in endogenous Axin indicate that its docking at LRP6 is antagonized by a phospho-dependent foldback within LIR and by a PRTxR motif that allows Axin and GSK3 to form a multi-pronged interaction which favors their detachment from LRP6. Crucially, signaling by LRP6 also depends on its binding to the AP2 clathrin adaptor. We propose that the Wnt-driven clustering of LRP6 within clathrin-coated locales allows the Axin-GSK complex to dock at adjacent LRP6 molecules, while also exposing it to co-targeted kinases that change its activity in Wnt signal transduction.
Gammons et al. describe how the clustering of the Wnt receptor complex in clathrin-coated locales allows Axin and GSK3 to dock at adjacent tails of the LRP6 co-receptor to assemble a signalosome that transduces the Wnt signal to the nucleus.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 101/6
/ 13/109
/ 13/31
/ 13/95
/ 38/1
/ 38/35
/ 38/44
/ 38/70
/ 38/77
/ 82/29
/ 82/80
/ 82/83
/ 96
/ Adapters
/ Adaptor Protein Complex 2 - metabolism
/ Clathrin
/ CRISPR
/ Foldback
/ Glycogen Synthase Kinase 3 - metabolism
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Low Density Lipoprotein Receptor-Related Protein-6 - chemistry
/ Low Density Lipoprotein Receptor-Related Protein-6 - genetics
/ Low Density Lipoprotein Receptor-Related Protein-6 - metabolism
/ Magnetic resonance spectroscopy
/ NMR
/ Science
