Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1

• Published in: Nature structural & molecular biology Vol. 18; no. 8; pp. 886 - 893
• Main Authors: Siebold, Christian, Jones, E Yvonne, Malinauskas, Tomas, Aricescu, A Radu, Lu, Weixian
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.08.2011
• Subjects: Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Amino Acid Motifs; Binding Sites; Binding sites (Biochemistry); Cell adhesion & migration; Cellular signal transduction; Crystal structure; Glycosaminoglycans - chemistry; Glycosaminoglycans - metabolism; HEK293 Cells; Homeostasis; Humans; Ligands; Lipid Metabolism; Models, Molecular; Molecular biology; Morphogenesis; Physiological aspects; Protein Folding; Protein Structure, Tertiary; Repressor Proteins - chemistry; Repressor Proteins - metabolism; Repressor Proteins - physiology; Signal Transduction; Wnt proteins; Wnt Proteins - chemistry; Wnt Proteins - physiology; United Kingdom
• ISSN: 1545-9993; 1545-9985
• DOI: 10.1038/nsmb.2081

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.