Wnt signalosome assembly is governed by conformational flexibility of Axin and by the AP2 clathrin adaptor

Melissa V. Gammons (), Elsa Franco-Echevarría, Tie-Mei Li, Trevor J. Rutherford, Miha Renko, Christopher Batters and Mariann Bienz ()
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Melissa V. Gammons: Francis Crick Avenue Cambridge
Elsa Franco-Echevarría: Francis Crick Avenue Cambridge
Tie-Mei Li: Francis Crick Avenue Cambridge
Trevor J. Rutherford: Francis Crick Avenue Cambridge
Miha Renko: Francis Crick Avenue Cambridge
Christopher Batters: Francis Crick Avenue Cambridge
Mariann Bienz: Francis Crick Avenue Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59984-9

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