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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 publication

DOI

10.1038/nsmb.2081

Type

Journal article

Journal

Nat Struct Mol Biol

Publication Date

10/07/2011

Volume

18

Pages

886 - 893

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