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| | ==Crystal structure of the cysteine-rich domain of human Frizzled 4 - Crystal Form I== | | ==Crystal structure of the cysteine-rich domain of human Frizzled 4 - Crystal Form I== |
| - | <StructureSection load='5bpb' size='340' side='right' caption='[[5bpb]], [[Resolution|resolution]] 2.20Å' scene=''> | + | <StructureSection load='5bpb' size='340' side='right'caption='[[5bpb]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5bpb]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BPB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5BPB FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5bpb]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5BPB OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BPB FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.2Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5bpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bpb OCA], [http://pdbe.org/5bpb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5bpb RCSB], [http://www.ebi.ac.uk/pdbsum/5bpb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5bpb ProSAT]</span></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5bpb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bpb OCA], [https://pdbe.org/5bpb PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bpb RCSB], [https://www.ebi.ac.uk/pdbsum/5bpb PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bpb ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/FZD4_HUMAN FZD4_HUMAN]] Retinopathy of prematurity;Familial exudative vitreoretinopathy;Persistent hyperplastic primary vitreous. The disease is caused by mutations affecting the gene represented in this entry. | + | [https://www.uniprot.org/uniprot/FZD4_HUMAN FZD4_HUMAN] Retinopathy of prematurity;Familial exudative vitreoretinopathy;Persistent hyperplastic primary vitreous. The disease is caused by mutations affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FZD4_HUMAN FZD4_HUMAN]] Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. | + | [https://www.uniprot.org/uniprot/FZD4_HUMAN FZD4_HUMAN] Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Chang, T H]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Harlos, K]] | + | [[Category: Large Structures]] |
| - | [[Category: Hsieh, F L]] | + | [[Category: Chang T-H]] |
| - | [[Category: Jones, E Y]] | + | [[Category: Harlos K]] |
| - | [[Category: G protein coupled receptor]] | + | [[Category: Hsieh F-L]] |
| - | [[Category: Glycoprotein]] | + | [[Category: Jones EY]] |
| - | [[Category: Receptor for norrin recognition]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Wnt signalling pathway]]
| + | |
| Structural highlights
Disease
FZD4_HUMAN Retinopathy of prematurity;Familial exudative vitreoretinopathy;Persistent hyperplastic primary vitreous. The disease is caused by mutations affecting the gene represented in this entry.
Function
FZD4_HUMAN Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin (CTNNB1) canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin (CTNNB1) and activation of Wnt target genes. Plays a critical role in retinal vascularization by acting as a receptor for Wnt proteins and norrin (NDP). In retina, it can be both activated by Wnt protein-binding, but also by a Wnt-independent signaling via binding of norrin (NDP), promoting in both cases beta-catenin (CTNNB1) accumulation and stimulation of LEF/TCF-mediated transcriptional programs. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.
Publication Abstract from PubMed
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 (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.
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 Elife. 2015 Jul 9;4. doi: 10.7554/eLife.06554. PMID:26158506[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chang TH, Hsieh FL, Zebisch M, Harlos K, Elegheert J, Jones EY. Structure and functional properties of Norrin mimic Wnt for signalling with Frizzled4, Lrp5/6, and proteoglycan. Elife. 2015 Jul 9;4. doi: 10.7554/eLife.06554. PMID:26158506 doi:http://dx.doi.org/10.7554/eLife.06554
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