21KT
Wnt3a signalosome extracellular complex
Summary for 21KT
| Entry DOI | 10.2210/pdb21kt/pdb |
| EMDB information | 67780 |
| Descriptor | Protein Wnt-3a, Frizzled-8,Peptidyl-prolyl cis-trans isomerase FKBP1A, Low-density lipoprotein receptor-related protein 6,Serine/threonine-protein kinase mTOR, ... (5 entities in total) |
| Functional Keywords | wnt3a-fzd8-lrp6 extracellular complex, cryo-em structure, fkbp-independent wnt3a homodimer, signaling protein |
| Biological source | Mus musculus (house mouse) More |
| Total number of polymer chains | 8 |
| Total formula weight | 366540.15 |
| Authors | |
| Primary citation | Yue, D.,Sun, G.,Cao, Y.,Li, H.,Yang, Y.,Pan, Z.,Xue, L.,Zhang, L.,Wang, Z.,Xu, W. Structural basis of Wnt signalosome extracellular complex assembly. Cell, 2026 Cited by 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 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. PubMed: 42202788DOI: 10.1016/j.cell.2026.05.006 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.33 Å) |
Structure validation
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