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| - | ==TERNARY WNT SIGNALLING COMPLEX== | + | |
| - | <StructureSection load='4ufs' size='340' side='right' caption='[[4ufs]], [[Resolution|resolution]] 4.80Å' scene=''> | + | ==Low resolution structure R-spondin-2 (Fu1Fu2) in complex with the ectodomains of LGR5 and ZNRF3== |
| | + | <StructureSection load='4ufs' size='340' side='right'caption='[[4ufs]], [[Resolution|resolution]] 4.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ufs]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4UFS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4UFS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ufs]] is a 3 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=4UFS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4UFS FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4ufr|4ufr]]</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]] 4.8Å</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=4ufs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ufs OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ufs RCSB], [http://www.ebi.ac.uk/pdbsum/4ufs PDBsum]</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=4ufs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ufs OCA], [https://pdbe.org/4ufs PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ufs RCSB], [https://www.ebi.ac.uk/pdbsum/4ufs PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ufs ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/LGR5_HUMAN LGR5_HUMAN]] Orphan receptor. Stem cell marker of the intestinal epithelium and the hair follicle. Target gene of Wnt signaling. [[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_MOUSE RSPO2_MOUSE]] 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. Also regulates the canonical Wnt/beta-catenin-dependent pathway and non-canonical Wnt signaling by acting as an inhibitor of ZNRF3, an important regulator of the Wnt signaling pathway. Probably also acts as a ligand for frizzled and LRP receptors.<ref>PMID:21693646</ref> | + | [https://www.uniprot.org/uniprot/LGR5_HUMAN LGR5_HUMAN] Orphan receptor. Stem cell marker of the intestinal epithelium and the hair follicle. Target gene of Wnt signaling. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4ufs" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Jones, E Y]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Zebisch, M]] | + | [[Category: Large Structures]] |
| - | [[Category: Lgr]] | + | [[Category: Jones EY]] |
| - | [[Category: Rspo]] | + | [[Category: Zebisch M]] |
| - | [[Category: Signaling protein]]
| + | |
| - | [[Category: Wnt]]
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| Structural highlights
Function
LGR5_HUMAN Orphan receptor. Stem cell marker of the intestinal epithelium and the hair follicle. Target gene of Wnt signaling.
Publication Abstract from PubMed
The four secreted R-spondin (Rspo1-4) proteins of vertebrates function as stem cell growth factors and potentiate canonical Wnt signalling. Rspo proteins act by cross-linking members of two cell surface receptor families, complexing the stem cell markers LGR4-6 with the Frizzled-specific E3 ubiquitin ligases ZNRF3/RNF43. The consequent internalisation of the ternary LGR-Rspo-E3 complex removes the E3 ligase activity, which otherwise targets the Wnt receptor Frizzled for degradation, and thus enhances Wnt signalling. Multiple combinations of LGR4-6, Rspo1-4 and ZNRF3/RNF43 are possible, implying the existence of generic interaction determinants, but also of specific differences in complex architecture and activity. We present here a high resolution crystal structure of an ectodomain variant of human LGR5 (hLGR5ecto) complexed with a signalling competent fragment of mouse Rspo2 (mRspo2Fu1-Fu2). The structure shows that the particularly potent Rspo2 ligand engages LGR5 in a fashion almost identical to that reported for hRSPO1. Comparison of our hLGR5ecto structure with previously published structures highlights a surprising plasticity of the LGR ectodomains, characterised by a nearly 9 degrees or larger rotation of the N-terminal half of the horseshoe-like fold relative to the C-terminal half. We also report a low resolution hLGR5-mRspo2Fu1-Fu2-mZNRF3ecto ternary complex structure. This crystal structure confirms our previously suggested hypothesis, showing that Rspo proteins cross-link LGRs and ZNRF3 into a 2:2:2 complex, whereas a 1:1:1 complex is formed with RNF43.
Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3.,Zebisch M, Yvonne Jones E J Struct Biol. 2015 Jun 26. pii: S1047-8477(15)00137-9. doi:, 10.1016/j.jsb.2015.05.008. PMID:26123262[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zebisch M, Yvonne Jones E. Crystal structure of R-spondin 2 in complex with the ectodomains of its receptors LGR5 and ZNRF3. J Struct Biol. 2015 Jun 26. pii: S1047-8477(15)00137-9. doi:, 10.1016/j.jsb.2015.05.008. PMID:26123262 doi:http://dx.doi.org/10.1016/j.jsb.2015.05.008
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