Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1

Tomas Malinauskas, Alexandru R Aricescu, Weixian Lu, Christian Siebold, E Yvonne Jones

Research output: Contribution to journalArticlepeer-review

Abstract

Wnt morphogens control embryonic development and homeostasis in adult tissues. In vertebrates the N-terminal WIF domain (WIF-1(WD)) of Wnt inhibitory factor 1 (WIF-1) binds Wnt ligands. Our crystal structure of WIF-1(WD) reveals a previously unidentified binding site for phospholipid; two acyl chains extend deep into the domain, and the head group is exposed to the surface. Biophysical and cellular assays indicate that there is a WIF-1(WD) Wnt-binding surface proximal to the lipid head group but also implicate the five epidermal growth factor (EGF)-like domains (EGFs I-V) in Wnt binding. The six-domain WIF-1 crystal structure shows that EGFs I-V are wrapped back, interfacing with WIF-1(WD) at EGF III. EGFs II-V contain a heparan sulfate proteoglycan (HSPG)-binding site, consistent with conserved positively charged residues on EGF IV. This combination of HSPG- and Wnt-binding properties suggests a modular model for the localization of WIF-1 and for signal inhibition within morphogen gradients.
Original languageEnglish
Pages (from-to)886-93
Number of pages8
JournalNature Structural & Molecular Biology
Volume18
Issue number8
Early online date10 Jul 2011
DOIs
Publication statusPublished - Jul 2011

Keywords

  • Adaptor Proteins, Signal Transducing
  • Amino Acid Motifs
  • Binding Sites
  • GLYCOSAMINOGLYCANS
  • HEK293 Cells
  • HUMANS
  • Lipid Metabolism
  • Models, Molecular
  • Protein Folding
  • Protein Structure, Tertiary
  • Repressor Proteins
  • Signal Transduction
  • Wnt Proteins

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