Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan
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-den...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2015-07-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/06554 |
| _version_ | 1811200400056909824 |
|---|---|
| author | Tao-Hsin Chang Fu-Lien Hsieh Matthias Zebisch Karl Harlos Jonathan Elegheert E Yvonne Jones |
| author_facet | Tao-Hsin Chang Fu-Lien Hsieh Matthias Zebisch Karl Harlos Jonathan Elegheert E Yvonne Jones |
| author_sort | Tao-Hsin Chang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:02:47Z |
| format | Article |
| id | doaj.art-ca5c6647a1d847f69bec7aa0c72fda41 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:02:47Z |
| publishDate | 2015-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-ca5c6647a1d847f69bec7aa0c72fda412022-12-22T03:52:37ZengeLife Sciences Publications LtdeLife2050-084X2015-07-01410.7554/eLife.06554Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycanTao-Hsin Chang0Fu-Lien Hsieh1Matthias Zebisch2Karl Harlos3Jonathan Elegheert4E Yvonne Jones5Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomDivision of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United KingdomWnt 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.https://elifesciences.org/articles/06554Wnt signallingcystine-knot growth factorretinal diseaseangiogenesiscrystal structureblood brain barrier |
| spellingShingle | Tao-Hsin Chang Fu-Lien Hsieh Matthias Zebisch Karl Harlos Jonathan Elegheert E Yvonne Jones Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan eLife Wnt signalling cystine-knot growth factor retinal disease angiogenesis crystal structure blood brain barrier |
| title | Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan |
| title_full | Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan |
| title_fullStr | Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan |
| title_full_unstemmed | Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan |
| title_short | Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan |
| title_sort | structure and functional properties of norrin mimic wnt for signalling with frizzled4 lrp5 6 and proteoglycan |
| topic | Wnt signalling cystine-knot growth factor retinal disease angiogenesis crystal structure blood brain barrier |
| url | https://elifesciences.org/articles/06554 |
| work_keys_str_mv | AT taohsinchang structureandfunctionalpropertiesofnorrinmimicwntforsignallingwithfrizzled4lrp56andproteoglycan AT fulienhsieh structureandfunctionalpropertiesofnorrinmimicwntforsignallingwithfrizzled4lrp56andproteoglycan AT matthiaszebisch structureandfunctionalpropertiesofnorrinmimicwntforsignallingwithfrizzled4lrp56andproteoglycan AT karlharlos structureandfunctionalpropertiesofnorrinmimicwntforsignallingwithfrizzled4lrp56andproteoglycan AT jonathanelegheert structureandfunctionalpropertiesofnorrinmimicwntforsignallingwithfrizzled4lrp56andproteoglycan AT eyvonnejones structureandfunctionalpropertiesofnorrinmimicwntforsignallingwithfrizzled4lrp56andproteoglycan |