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XB-ART-50980
Elife July 9, 2015; 4

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

Chang TH , Hsieh FL , Zebisch M , Harlos K , Elegheert J , Jones EY .


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.

PubMed ID: 26158506
PMC ID: PMC4497409
Article link: Elife
Grant support: [+]
Genes referenced: aopep bmp2 bmp7.1 flt4 frzb frzb2 fst fzd4 fzd8 lrp5 mbp mstn.1 musk ncr3 ndp nog pam pdgfa rho rho.2 sfrp1 sfrp2 sfrp4 sfrp5 smo spr szl tbx2 vegfa vegfc wnt8a


Article Images: [+] show captions
References:
Adams, 2010, Pubmed [+]


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