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| Title | Structural basis of Wnt signalosome extracellular complex assembly. |
|---|---|
| Journal, issue, pages | Cell, Year 2026 |
| Publish date | May 27, 2026 |
Authors | Dan Yue / Gangyu Sun / Yunlong Cao / Hongyue Li / Yufeng Yang / Zirun Pan / Lulu Xue / Lu Zhang / Zhizhi Wang / Wenqing Xu / ![]() |
| PubMed Abstract | 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 ...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 links | Cell / PubMed:42202788 |
| Methods | EM (single particle) |
| Resolution | 2.9 - 3.33 Å |
| Structure data | EMDB-67778, PDB-21kr: EMDB-67779, PDB-21ks: EMDB-67780, PDB-21kt: |
| Chemicals | ![]() ChemComp-NAG: ![]() ChemComp-RAP: |
| Source |
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Keywords | SIGNALING PROTEIN / Wnt3a-Fzd8-LRP6 extracellular complex / Cryo-EM structure / FKBP-stabilized Wnt3a homodimer / FKBP-independent Wnt3a homodimer |
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homo sapiens (human)
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