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| | ==Crystal structure of XWnt8 in complex with the cysteine-rich domain of Frizzled 8== | | ==Crystal structure of XWnt8 in complex with the cysteine-rich domain of Frizzled 8== |
| - | <StructureSection load='4f0a' size='340' side='right' caption='[[4f0a]], [[Resolution|resolution]] 3.25Å' scene=''> | + | <StructureSection load='4f0a' size='340' side='right'caption='[[4f0a]], [[Resolution|resolution]] 3.25Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4f0a]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/African_clawed_frog African clawed frog] and [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F0A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4F0A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4f0a]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Xenopus_laevis Xenopus laevis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4F0A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4F0A FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=PAM:PALMITOLEIC+ACID'>PAM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PAM:PALMITOLEIC+ACID'>PAM</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ijy|1ijy]]</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=4f0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f0a OCA], [https://pdbe.org/4f0a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4f0a RCSB], [https://www.ebi.ac.uk/pdbsum/4f0a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4f0a ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Fzd8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice]), wnt8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=8355 African clawed frog])</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=4f0a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4f0a OCA], [http://pdbe.org/4f0a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4f0a RCSB], [http://www.ebi.ac.uk/pdbsum/4f0a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4f0a ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/FZD8_MOUSE FZD8_MOUSE]] Receptor for Wnt proteins. Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes (By similarity). The beta-catenin canonical signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. 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. Coreceptor along with RYK of Wnt proteins, such as WNT1.<ref>PMID:10395542</ref> <ref>PMID:10097073</ref> <ref>PMID:15454084</ref> <ref>PMID:16543246</ref> [[http://www.uniprot.org/uniprot/WNT8_XENLA WNT8_XENLA]] Ligand for members of the frizzled family of seven transmembrane receptors. Plays a role in ventral mesodermal patterning during embryogenesis. Mimics Nieuwkoop center activity. Causes dorsal mesodermal differentiation of animal cap ectoderm when coexpressed with noggin and nuclear, sequence-specific DNA-binding protein xBra. None of these molecules causes dorsal mesoderm formation when expressed alone.<ref>PMID:7906224</ref> | + | [https://www.uniprot.org/uniprot/FZD8_MOUSE FZD8_MOUSE] Receptor for Wnt proteins. Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes (By similarity). The beta-catenin canonical signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. 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. Coreceptor along with RYK of Wnt proteins, such as WNT1.<ref>PMID:10395542</ref> <ref>PMID:10097073</ref> <ref>PMID:15454084</ref> <ref>PMID:16543246</ref> |
| | <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: African clawed frog]] | + | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Garcia, K C]] | + | [[Category: Xenopus laevis]] |
| - | [[Category: Janda, C Y]] | + | [[Category: Garcia KC]] |
| - | [[Category: Levin, A M]] | + | [[Category: Janda CY]] |
| - | [[Category: Thomas, C]] | + | [[Category: Levin AM]] |
| - | [[Category: Waghray, D]] | + | [[Category: Thomas C]] |
| - | [[Category: Fatty acid acylation]]
| + | [[Category: Waghray D]] |
| - | [[Category: Frizzled]]
| + | |
| - | [[Category: Glycosylation]]
| + | |
| - | [[Category: Ligand-receptor complex]]
| + | |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Wnt]]
| + | |
| - | [[Category: Wnt signaling]]
| + | |
| Structural highlights
4f0a is a 2 chain structure with sequence from Mus musculus and Xenopus laevis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
FZD8_MOUSE Receptor for Wnt proteins. Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalsomes (By similarity). The beta-catenin canonical signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. 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. Coreceptor along with RYK of Wnt proteins, such as WNT1.[1] [2] [3] [4]
Publication Abstract from PubMed
Wnts are lipid-modified morphogens that play critical roles in development principally through engagement of Frizzled receptors. The 3.25 A structure of Xenopus Wnt8 (XWnt8) in complex with mouse Frizzled-8 cysteine-rich domain (CRD) reveals an unusual two-domain Wnt structure, not obviously related to known protein folds, resembling a "hand" with "thumb" and "index" fingers extended to grasp the Fz8-CRD at two distinct binding sites. One site is dominated by a palmitoleic acid lipid group projecting from Serine 187 at the tip of Wnt's thumb into a deep groove in the Fz8-CRD. In the second binding site, the conserved tip of Wnt's "index finger" forms hydrophobic amino acid contacts with a depression on the opposite side of the Fz8-CRD. The conservation of amino acids in both interfaces appears to facilitate ligand-receptor cross-reactivity, which has important implications for understanding Wnt's functional pleiotropy and for developing Wnt-based drugs for cancer and regenerative medicine.
Structural Basis of Wnt Recognition by Frizzled.,Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC Science. 2012 May 31. PMID:22653731[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sheldahl LC, Park M, Malbon CC, Moon RT. Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Curr Biol. 1999 Jul 1;9(13):695-8. PMID:10395542
- ↑ Hsieh JC, Rattner A, Smallwood PM, Nathans J. Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3546-51. PMID:10097073
- ↑ Lu W, Yamamoto V, Ortega B, Baltimore D. Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth. Cell. 2004 Oct 1;119(1):97-108. PMID:15454084 doi:10.1016/j.cell.2004.09.019
- ↑ Nam JS, Turcotte TJ, Smith PF, Choi S, Yoon JK. Mouse cristin/R-spondin family proteins are novel ligands for the Frizzled 8 and LRP6 receptors and activate beta-catenin-dependent gene expression. J Biol Chem. 2006 May 12;281(19):13247-57. Epub 2006 Mar 16. PMID:16543246 doi:10.1074/jbc.M508324200
- ↑ Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC. Structural Basis of Wnt Recognition by Frizzled. Science. 2012 May 31. PMID:22653731 doi:10.1126/science.1222879
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