Structural Basis of WLS/Evi-Mediated Wnt Transport and Secretion.

Journal Article (Journal Article)

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 Wntless/evenness interrupted (WLS/Evi). We report the 3.2 Å resolution cryogenic electron microscopy (cryo-EM) structure of palmitoleated human WNT8A in complex with WLS. This is 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 (GPCRs). A Wnt hairpin inserts into a conserved hydrophobic cavity in the GPCR-like domain, and the palmitoleate protrudes between two helices into the bilayer. A conformational switch of highly conserved residues on a separate Wnt hairpin might 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.

Full Text

Duke Authors

Cited Authors

  • Nygaard, R; Yu, J; Kim, J; Ross, DR; Parisi, G; Clarke, OB; Virshup, DM; Mancia, F

Published Date

  • January 7, 2021

Published In

Volume / Issue

  • 184 / 1

Start / End Page

  • 194 - 206.e14

PubMed ID

  • 33357447

Pubmed Central ID

  • PMC7797000

Electronic International Standard Serial Number (EISSN)

  • 1097-4172

Digital Object Identifier (DOI)

  • 10.1016/j.cell.2020.11.038

Language

  • eng

Conference Location

  • United States