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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
PMID:
26158506
Authors:
Tao-Hsin
Chang
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
Fu-Lien
Hsieh
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
Matthias
Zebisch
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
Karl
Harlos
(Wellcome Trust Centre for Human Genetics, University of Oxford)
,
Jonathan
Elegheert
(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:
Elife
, VOL 4
State:
Published (Approved)
Published:
July 2015
Diamond Proposal Number(s):
10627

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,
Medicine
Instruments:
I03-Macromolecular Crystallography
,
I04-1-Macromolecular Crystallography (fixed wavelength)
,
I04-Macromolecular Crystallography
,
I24-Microfocus Macromolecular Crystallography
Other Facilities: Synchrotron Radiation Facility (beamline BM29)
Added On:
23/09/2015 12:05
Documents:
elife-06554-v1.pdf
Discipline Tags:
Health & Wellbeing
Structural biology
Ophthalmology
Drug Discovery
Life Sciences & Biotech
Technical Tags:
Diffraction
Macromolecular Crystallography (MX)