title: Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1.
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.
authors: Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
authors: Tomas
authors: T
authors: Malinauskas
authors: A Radu
authors: AR
authors: Aricescu
authors: Weixian
authors: W
authors: Lu
authors: Christian
authors: C
authors: Siebold
authors: E Yvonne
authors: EY
authors: Jones
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D020816:Amino Acid Motifs; D001665:Binding Sites; D006025:Glycosaminoglycans / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism; D008958:Models, Molecular; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D051153:Wnt Proteins / Q000737:chemistry / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006025:Glycosaminoglycans; D012097:Repressor Proteins; C485569:WIF1 protein, human; D051153:Wnt Proteins