期刊
ELIFE
卷 4, 期 -, 页码 -出版社
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.06554
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资金
- Wellcome Trust [090532/Z/09/Z]
- Cancer Research UK [C375/A10976]
- Medical Research Council [G0900084]
- Cancer Research UK [10976, 17721] Funding Source: researchfish
- Medical Research Council [G0900084] Funding Source: researchfish
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/beta-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 (Fz4(CRD)), of this complex bound with GAG analogues, and of unliganded Norrin and Fz4(CRD). 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 Fz4(CRD). These results explain numerous disease-associated mutations. Comparison with the Xenopus Wnt8-mouse Fz8(CRD) 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.
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