PXD061649-1

PXD061649 is an original dataset announced via ProteomeXchange.

Title	Wnt signalosome assembly is governed by conformational flexibility of Axin and AP2 clathrin adaptor
Description	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.
HostingRepository	PRIDE
AnnounceDate	2025-04-30
AnnouncementXML	Submission_2025-04-30_03:22:48.311.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mariann Bienz
SpeciesList	scientific name: Xenopus laevis (African clawed frog); NCBI TaxID: 8355;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2025-03-10 07:18:56	ID requested
⏵ 1	2025-04-30 03:22:48	announced

Dataset with its publication pending

submitter keyword: GSK3 inhibition

LRP6 co-receptor

Axin scaffold protein

AP2 cargo adaptor

clathrin-coated structures

Wnt signalosome

Mariann Bienz
contact affiliation	MRC Laboratory of Molecular Biology Francis Crick Avenue Cambridge Biomedical Campus CB2 0QH Cambridge UK
contact email	mb2@mrc-lmb.cam.ac.uk
lab head
Mariann Bienz
contact affiliation	MRC Laboratory of Molecular Biology
contact email	mb2@mrc-lmb.cam.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD061649
     1. Label: PRIDE project
     2. Name: Wnt signalosome assembly is governed by conformational flexibility of Axin and AP2 clathrin adaptor