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.
Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1.,Malinauskas T, Aricescu AR, Lu W, Siebold C, Jones EY Nat Struct Mol Biol. 2011 Jul 10;18(8):886-93. doi: 10.1038/nsmb.2081. PMID:21743455[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
↑ Malinauskas T, Aricescu AR, Lu W, Siebold C, Jones EY. Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1. Nat Struct Mol Biol. 2011 Jul 10;18(8):886-93. doi: 10.1038/nsmb.2081. PMID:21743455 doi:10.1038/nsmb.2081
