Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1.

Journal article

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.

Authors: Malinauskas, T; Aricescu, A; Lu, W; Siebold, C; Jones, E

• Publication status: Published
• Journal: Nature structural and molecular biology
• Volume: 18
• Issue: 8
• Pages: 886-893
• Publication date: 2011-08-01
• DOI: 10.1038/nsmb.2081
• EISSN: 1545-9985
• ISSN: 1545-9993
• Language: English
• Keywords: Wnt Proteins; Binding Sites; Amino Acid Motifs; Adaptor Proteins, Signal Transducing; Humans; Repressor Proteins; HEK293 Cells; Signal Transduction; Lipid Metabolism; Protein Folding; Glycosaminoglycans; Protein Structure, Tertiary; Models, Molecular