9Z4O

Cryo-EM structure of human Wntless in its apo state

Summary for 9Z4O

• Entry DOI: 10.2210/pdb9z4o/pdb
• EMDB information: 73810
• Descriptor: Protein wntless homolog (1 entity in total)
• Functional Keywords: wnt transporter, wnt secretion, wnt signaling, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 66088.14

Authors

Ge, Y.,de Almeida Magalhaes, T.,Wu, H.,Yadav, G.P.,Wang, Z.,Salic, A.,Jiang, J.,Huang, P. (deposition date: 2025-11-10, release date: 2026-06-10, Last modification date: 2026-07-01)

Primary citation

Ge, Y.,de Almeida Magalhaes, T.,Wu, H.,van den Boomen, D.J.H.,Nguyen, T.U.,Dou, T.,Yadav, G.P.,Lee, S.,Wang, Z.,Lemoff, A.,Luo, X.,Menon, S.S.,Zhang, M.,Wang, J.,Jin, Z.,Jiang, J.,Salic, A.,Huang, P.
Conformational cycling of the Wntless transporter drives trafficking and secretion of Wnt morphogens.
Nat Commun, 2026

PubMed Abstract: Wnt proteins are lipid-modified morphogens fundamental in development and disease. During Wnt biogenesis, the G-protein-coupled receptor (GPCR)-like transporter Wntless (WLS) escorts lipidated Wnts from the endoplasmic reticulum to the plasma membrane, then transfers them to extracellular carriers, forming active and soluble morphogen-carrier complexes. To dissect the mechanisms involved, we solve cryo-EM structures of Wnt-bound WLS and unliganded WLS, and perform structure-guided functional experiments. Wnts engage WLS via three conserved hairpins, which are all required for Wnt trafficking to the cell surface and carrier-mediated secretion. Wnt release from cells is driven by dramatic conformational changes in the WLS transmembrane domain, reminiscent of GPCR activation, together with WLS extracellular rearrangements. Unexpectedly, we find that Wnt5a bound to WLS forms dimers, with implications for Wnt signaling. These findings define the mechanism of WLS conformational cycling that governs the intracellular transport and extracellular release of Wnt morphogens, essential steps in the Wnt pathway.

PubMed: 42321207
DOI: 10.1038/s41467-026-74521-y

Experimental method

ELECTRON MICROSCOPY (2.63 Å)