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Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan

DOI: 10.7554/eLife.06554 DOI Help
PMID: 26158506 PMID Help

Authors: Tao-hsin Chang (University of Oxford) , Fu-lien Hsieh (University of Oxford) , Matthias Zebisch (University of Oxford) , Karl Harlos (Wellcome Trust Centre for Human Genetics, University of Oxford) , Jonathan Elegheert (Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford) , Edith Jones (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Elife , VOL 4

State: Published (Approved)
Published: July 2015
Diamond Proposal Number(s): 10627

Open Access Open Access

Abstract: Wnt signalling regulates multiple processes including angiogenesis, inflammation, and tumorigenesis. Norrin (Norrie Disease Protein) is a cystine-knot like growth factor. Although unrelated to Wnt, Norrin activates the Wnt/β-catenin pathway. Signal complex formation involves Frizzled4 (Fz4), low-density lipoprotein receptor related protein 5/6 (Lrp5/6), Tetraspanin-12 and glycosaminoglycans (GAGs). Here, we report crystallographic and small-angle X-ray scattering analyses of Norrin in complex with Fz4 cysteine-rich domain (Fz4CRD), of this complex bound with GAG analogues, and of unliganded Norrin and Fz4CRD. Our structural, biophysical and cellular data, map Fz4 and putative Lrp5/6 binding sites to distinct patches on Norrin, and reveal a GAG binding site spanning Norrin and Fz4CRD. These results explain numerous disease-associated mutations. Comparison with the Xenopus Wnt8–mouse Fz8CRD complex reveals Norrin mimics Wnt for Frizzled recognition. The production and characterization of wild-type and mutant Norrins reported here open new avenues for the development of therapeutics to combat abnormal Norrin/Wnt signalling.

Subject Areas: Biology and Bio-materials

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: Synchrotron Radiation Facility (beamline BM29)

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