Journal article
Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 6.5MB, Terms of use)
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- Publisher copy:
- 10.7554/elife.06554
Authors
+ Wellcome Trust
More from this funder
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 090532/Z/09/Z
- 10976
+ Cancer Research UK
More from this funder
- Funder identifier:
- https://ror.org/054225q67
- Grant:
- 17721
- 10976
+ Medical Research Council
More from this funder
- Funder identifier:
- https://ror.org/03x94j517
- Grant:
- G0900084
- Publisher:
- eLife Sciences Publications
- Journal:
- eLife More from this journal
- Volume:
- 4
- Article number:
- e06554
- Place of publication:
- England
- Publication date:
- 2015-07-09
- Acceptance date:
- 2015-06-18
- DOI:
- EISSN:
-
2050-084X
- Pmid:
-
26158506
- Language:
-
English
- Keywords:
- Pubs id:
-
531703
- Local pid:
-
pubs:531703
- Deposit date:
-
2025-02-18
Terms of use
- Copyright holder:
- Chang et al.
- Copyright date:
- 2015
- Rights statement:
- © 2015 Chang et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
- Licence:
- CC Attribution (CC BY)
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