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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.

Original publication

DOI

10.7554/eLife.06554

Type

Journal article

Journal

Elife

Publication Date

09/07/2015

Volume

4

Keywords

Wnt signalling, angiogenesis, biophysics, blood brain barrier, crystal structure, cystine-knot growth factor, developmental biology, human, mouse, retinal disease, stem cells, structural biology, Binding Sites, Crystallography, X-Ray, Eye Proteins, Frizzled Receptors, Humans, Low Density Lipoprotein Receptor-Related Protein-5, Low Density Lipoprotein Receptor-Related Protein-6, Mutant Proteins, Nerve Tissue Proteins, Protein Conformation, Proteoglycans, Scattering, Small Angle