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

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 that favors their detachment from LRP6. Crucially, signaling by LRP6 also depends on its binding to 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.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Xenopus Laevis (african Clawed Frog)

TISSUE(S): Early Embryonic Cell, Diploid Cell

SUBMITTER: Mariann Bienz

LAB HEAD: Mariann Bienz

PROVIDER: PXD061649 | Pride | 2025-04-30

REPOSITORIES: Pride

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			Action	DRS
	MMW4894A10LC3B2MMW4894A10LC340233090.raw	Raw
	MMW4894A11LC3C2MMW4894A11LC340233091.raw	Raw
	MMW4894A12LC3D2MMW4894A12LC340233092.raw	Raw
	MMW4894A13LC3E2MMW4894A13LC340233093.raw	Raw
	MMW4894A14LC3F2MMW4894A14LC340233094.raw	Raw

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