Structural basis of WLS/Evi-mediated Wnt transport and secretion

By R. Nygaard, Jia Yu, Jonathan Kim, Daniela Ross, G. Parisi, O. Clarke, D. Virshup, F. Mancia. 2020

66 citations recorded by the source corpus.

SUMMARY Wnts are evolutionarily conserved ligands that signal at short range to regulate morphogenesis, cell fate and stem cell renewal. The first and essential steps in Wnt secretion are their O-palmitoleation and subsequent loading onto the dedicated transporter WLS/Evi. We report the 3.2 Å resolution cryo-EM structure of palmitoleated human WNT8A in complex with WLS accompanied by biochemical experiments to probe the physiological implications of the observed association. The WLS membrane domain has close structural homology to G protein-coupled receptors (GPCR). A Wnt hairpin inserts into a conserved hydrophobic cavity in the GPCR-like domain with the palmitoleate protruding between two helices into the bilayer. A conformational switch of highly conserved residues on a separate Wnt hairpin may contribute to its transfer to receiving cells. This work provides molecular-level insights into a central mechanism in animal body plan development and stem cell biology.

Subfields: Genetics, Molecular Biology

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In Molecular Biology

1. Jia Yu
2. D. Virshup

Citations in the corpus

• Structural model of PORCN illuminates disease-associated variants and drug binding sites (2021, methodology): “To predict protein-protein interactions, the structure of WNT8A was extracted from the WLS/WNT8A structure (PDB 7KC4) (Nygaard et al., 2021) and the ClusPro 2.0 Server (Kozakov et al., 2017) was used to predict its interaction with PORCN.”