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Structure paper

TitleStructural basis of Wnt signalosome extracellular complex assembly.
Journal, issue, pagesCell, Year 2026
Publish dateMay 27, 2026
AuthorsDan Yue / Gangyu Sun / Yunlong Cao / Hongyue Li / Yufeng Yang / Zirun Pan / Lulu Xue / Lu Zhang / Zhizhi Wang / Wenqing Xu /
PubMed AbstractRecognition of Wnt proteins by Frizzled (Fzd) receptors and the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptor is essential for canonical Wnt signaling. It remains ...Recognition of Wnt proteins by Frizzled (Fzd) receptors and the low-density lipoprotein receptor-related protein 5/6 (LRP5/6) co-receptor is essential for canonical Wnt signaling. It remains enigmatic how Wnt simultaneously interacts with Fzd and LRP5/6 and activates intracellular Wnt/β-catenin signaling. Here, we report cryo-electron microscopy (cryo-EM) structures of Wnt3a/Fzd8/LRP6 extracellular complexes captured in a 2:4:2 stoichiometry, consisting of a Wnt3a-Wnt3a homodimer, whereby each Wnt3a monomer binds to two Fzd8 receptors and one LRP6 co-receptor. This implies that Wnt3a induces Fzd cystine-rich domain (Fzd-CRD) tetramerization, which in turn could promote recruitment of oligomeric Disheveled (Dvl) to Fzd on the cytoplasmic side. Indeed, mutations of key Wnt3a-Wnt3a interface residues abolish Fzd-LRP clustering and downstream signaling, supporting a critical role of Wnt3a-Wnt3a dimerization in Wnt signalosome assembly and signaling. Our structures also show how the Wnt3a N-helical domain recognizes the LRP6 extracellular domain (LRP6-ECD) E3 β-propeller, while the Wnt3a N-C hairpin interacts with the valley between LRP6-E3 and -E4 propellers, underpinning the development of targeted Wnt therapeutics.
External linksCell / PubMed:42202788
MethodsEM (single particle)
Resolution2.9 - 3.33 Å
Structure data

67778

21kr

EMDB-67778, PDB-21kr:
A Wnt3a/Fzd8-CRD/LRP6-E3E4 complex with FKBP
Method: EM (single particle) / Resolution: 2.9 Å

67779

21ks

EMDB-67779, PDB-21ks:
A Wnt3a/Fzd8-CRD/LRP6-E3E4-LA complex with FKBP
Method: EM (single particle) / Resolution: 3.01 Å

67780

21kt

EMDB-67780, PDB-21kt:
Wnt3a signalosome extracellular complex
Method: EM (single particle) / Resolution: 3.33 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-RAP:
RAPAMYCIN IMMUNOSUPPRESSANT DRUG / antibiotic*YM

Source
  • mus musculus (house mouse)
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / Wnt3a-Fzd8-LRP6 extracellular complex / Cryo-EM structure / FKBP-stabilized Wnt3a homodimer / FKBP-independent Wnt3a homodimer

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