Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1

DOI: 10.1038/nsmb.2081
PMID: 21743455

Authors: Tomas Malinauskas (Wellcome Trust Centre for Human Genetics, University of Oxford,) , Alexandru Aricescu (Wellcome Trust Centre for Human Genetics, University of Oxford,) , Weixian Lu (Wellcome Trust Centre for Human Genetics, University of Oxford,) , Christian Siebold (Wellcome Trust Centre for Human Genetics, University of Oxford,) , E. Yvonne Jones (Wellcome Trust Centre for Human Genetics, University of Oxford,)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology , VOL 18 (8) , PAGES 886-893

State: Published (Approved)
Published: December 2011

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.

Journal Keywords: Signal; Amino; Binding; Glycosaminoglycans; HEK293; Humans; Lipid; Models; Molecular; Protein; Tertiary; Repressor; Signal; Wnt Proteins

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ID23.2 at ESRF

Added On: 04/04/2012 12:08

Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)