21KS

A Wnt3a/Fzd8-CRD/LRP6-E3E4-LA complex with FKBP

This is a non-PDB format compatible entry.

Summary for 21KS

• Entry DOI: 10.2210/pdb21ks/pdb
• EMDB information: 67779
• Descriptor: Frizzled-8,Peptidyl-prolyl cis-trans isomerase FKBP1A, Protein Wnt-3a, Low-density lipoprotein receptor-related protein 6,Serine/threonine-protein kinase mTOR, ... (6 entities in total)
• Functional Keywords: wnt3a-fzd8-lrp6 extracellular complex, cryo-em structure, fkbp-stabilized wnt3a homodimer, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 9
• Total formula weight: 425553.76

Authors

Yue, D.,Sun, G.,Zhang, L.,Wang, Z.,Xu, W. (deposition date: 2025-12-17, release date: 2026-06-03)

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

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: 42202788
DOI: 10.1016/j.cell.2026.05.006

Experimental method

ELECTRON MICROSCOPY (3.01 Å)