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| | ==Mouse ZNRF3 ectodomain in complex with Xenopus RSPO2 Fu1-Fu2 (Seleno Met) crystal form I== | | ==Mouse ZNRF3 ectodomain in complex with Xenopus RSPO2 Fu1-Fu2 (Seleno Met) crystal form I== |
| - | <StructureSection load='4c9a' size='340' side='right' caption='[[4c9a]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='4c9a' size='340' side='right'caption='[[4c9a]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4c9a]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice] and [http://en.wikipedia.org/wiki/Silurana_(xenopus)_tropicalis Silurana (xenopus) tropicalis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C9A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C9A FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4c9a]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Xenopus_tropicalis Xenopus tropicalis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4C9A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C9A FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</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]] 2.4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c84|4c84]], [[4c85|4c85]], [[4c86|4c86]], [[4c8a|4c8a]], [[4c8c|4c8c]], [[4c8f|4c8f]], [[4c8p|4c8p]], [[4c8t|4c8t]], [[4c8u|4c8u]], [[4c8v|4c8v]], [[4c8w|4c8w]], [[4c99|4c99]], [[4c9e|4c9e]], [[4c9r|4c9r]], [[4c9u|4c9u]], [[4c9v|4c9v]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></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=4c9a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c9a OCA], [http://pdbe.org/4c9a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4c9a RCSB], [http://www.ebi.ac.uk/pdbsum/4c9a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4c9a ProSAT]</span></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=4c9a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c9a OCA], [https://pdbe.org/4c9a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c9a RCSB], [https://www.ebi.ac.uk/pdbsum/4c9a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c9a ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ZNRF3_MOUSE ZNRF3_MOUSE]] E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby resticting the size of the intestinal stem cell zone.<ref>PMID:22575959</ref> <ref>PMID:22895187</ref> [[http://www.uniprot.org/uniprot/RSPO2_XENTR RSPO2_XENTR]] Activator of the canonical Wnt signaling pathway by acting as a ligand for lgr4-6 receptors. Upon binding to lgr4-6 (lgr4, lgr5 or lgr6), lgr4-6 associate with phosphorylated lrp6 and frizzled receptors that are activated by extracellular Wnt receptors, triggering the canonical Wnt signaling pathway to increase expression of target genes. Acts both in the canonical. Wnt/beta-catenin-dependent pathway and in non-canonical Wnt signaling pathway. Activates neural markers and promotes muscle formation. Overexpression blocks activin, nodal and BMP4 signaling, suggesting that it may negatively regulate the TGF-beta pathway (By similarity). | + | [https://www.uniprot.org/uniprot/ZNRF3_MOUSE ZNRF3_MOUSE] E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby resticting the size of the intestinal stem cell zone.<ref>PMID:22575959</ref> <ref>PMID:22895187</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Ubiquitin protein ligase|Ubiquitin protein ligase]] | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Large Structures]] |
| - | [[Category: Jones, E Y]] | + | [[Category: Mus musculus]] |
| - | [[Category: Zebisch, M]] | + | [[Category: Xenopus tropicalis]] |
| - | [[Category: Lgr4]] | + | [[Category: Jones EY]] |
| - | [[Category: Lgr5]] | + | [[Category: Zebisch M]] |
| - | [[Category: Lgr6]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: R-spo]]
| + | |
| - | [[Category: R-spondin]]
| + | |
| - | [[Category: Receptor]]
| + | |
| - | [[Category: Rspo]]
| + | |
| - | [[Category: Rspo1]]
| + | |
| - | [[Category: Rspo2]]
| + | |
| - | [[Category: Rspo3]]
| + | |
| - | [[Category: Rspo4]]
| + | |
| - | [[Category: Signalling]]
| + | |
| - | [[Category: Wnt]]
| + | |
| Structural highlights
Function
ZNRF3_MOUSE E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination and subsequent degradation of Wnt receptor complex components Frizzled and LRP6. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby resticting the size of the intestinal stem cell zone.[1] [2]
Publication Abstract from PubMed
The four R-spondin (Rspo) proteins are secreted agonists of Wnt signalling in vertebrates, functioning in embryogenesis and adult stem cell biology. Through ubiquitination and degradation of Wnt receptors, the transmembrane E3 ubiquitin ligase ZNRF3 and related RNF43 antagonize Wnt signalling. Rspo ligands have been reported to inhibit the ligase activity through direct interaction with ZNRF3 and RNF43. Here we report multiple crystal structures of the ZNRF3 ectodomain (ZNRF3ecto), a signalling-competent Furin1-Furin2 (Fu1-Fu2) fragment of Rspo2 (Rspo2Fu1-Fu2), and Rspo2Fu1-Fu2 in complex with ZNRF3ecto, or RNF43ecto. A prominent loop in Fu1 clamps into equivalent grooves in the ZNRF3ecto and RNF43ecto surface. Rspo binding enhances dimerization of ZNRF3ecto but not of RNF43ecto. Comparison of the four Rspo proteins, mutants and chimeras in biophysical and cellular assays shows that their signalling potency depends on their ability to recruit ZNRF3 or RNF43 via Fu1 into a complex with LGR receptors, which interact with Rspo via Fu2.
Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin.,Zebisch M, Xu Y, Krastev C, Macdonald BT, Chen M, Gilbert RJ, He X, Jones EY Nat Commun. 2013 Nov 14;4:2787. doi: 10.1038/ncomms3787. PMID:24225776[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hao HX, Xie Y, Zhang Y, Charlat O, Oster E, Avello M, Lei H, Mickanin C, Liu D, Ruffner H, Mao X, Ma Q, Zamponi R, Bouwmeester T, Finan PM, Kirschner MW, Porter JA, Serluca FC, Cong F. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature. 2012 Apr 29;485(7397):195-200. doi: 10.1038/nature11019. PMID:22575959 doi:10.1038/nature11019
- ↑ Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, van Es JH, Mohammed S, Heck AJ, Maurice MM, Clevers H. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012 Aug 30;488(7413):665-9. doi: 10.1038/nature11308. PMID:22895187 doi:10.1038/nature11308
- ↑ Zebisch M, Xu Y, Krastev C, Macdonald BT, Chen M, Gilbert RJ, He X, Jones EY. Structural and molecular basis of ZNRF3/RNF43 transmembrane ubiquitin ligase inhibition by the Wnt agonist R-spondin. Nat Commun. 2013 Nov 14;4:2787. doi: 10.1038/ncomms3787. PMID:24225776 doi:http://dx.doi.org/10.1038/ncomms3787
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