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TitleConformational cycling of the Wntless transporter drives trafficking and secretion of Wnt morphogens.
Journal, issue, pagesNat Commun, Year 2026
Publish dateJun 19, 2026
AuthorsYunhui Ge / Taciani de Almeida Magalhaes / Hongjiang Wu / Dick J H van den Boomen / Thu Uyen Nguyen / Tongyi Dou / Gaya P Yadav / Sukyeong Lee / Zhao Wang / Andrew Lemoff / Xuemei Luo / Sumitha S Menon / Min Zhang / Jin Wang / Zhicheng Jin / Jiansen Jiang / Adrian Salic / Pengxiang Huang /
PubMed AbstractWnt 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 ...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.
External linksNat Commun / PubMed:42321207
MethodsEM (single particle)
Resolution2.63 - 3.38 Å
Structure data

EMDB-73803, PDB-9z4h:
Cryo-EM structure of human Wntless in complex with Wnt5a at 1:1 stoichiometry
Method: EM (single particle) / Resolution: 2.64 Å

EMDB-73810, PDB-9z4o:
Cryo-EM structure of human Wntless in its apo state
Method: EM (single particle) / Resolution: 2.63 Å

EMDB-73835: Cryo-EM structure of human Wntless-Wnt5a 2:2 complex - Focused map A
Method: EM (single particle) / Resolution: 3.38 Å

EMDB-73836: Cryo-EM structure of human Wntless-Wnt5a 2:2 complex - Focused map B
Method: EM (single particle) / Resolution: 3.25 Å

EMDB-73837: Cryo-EM structure of human Wntless-Wnt5a 2:2 complex - Consensus map
Method: EM (single particle) / Resolution: 3.32 Å

EMDB-73838, PDB-9z67:
Cryo-EM structure of human Wntless-Wnt5a 2:2 complex - Composite map
Method: EM (single particle) / Resolution: 3.32 Å

Chemicals

ChemComp-PAM:
PALMITOLEIC ACID

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

ChemComp-PCW:
1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / DOPC, phospholipid*YM

ChemComp-CLR:
CHOLESTEROL

ChemComp-LPE:
1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / Wnt transporter / Wnt5a / Wnt signaling / Wnt secretion

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