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| | ==Solution NMR structure of Tryptophan to Alanine mutant of Arkadia RING domain.== | | ==Solution NMR structure of Tryptophan to Alanine mutant of Arkadia RING domain.== |
| - | <StructureSection load='5lg0' size='340' side='right'caption='[[5lg0]], [[NMR_Ensembles_of_Models | 31 NMR models]]' scene=''> | + | <StructureSection load='5lg0' size='340' side='right'caption='[[5lg0]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5lg0]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LG0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5LG0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5lg0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5LG0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5LG0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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">[[2kiz|2kiz]], [[5lg7|5lg7]]</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=5lg0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lg0 OCA], [https://pdbe.org/5lg0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5lg0 RCSB], [https://www.ebi.ac.uk/pdbsum/5lg0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5lg0 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RNF111 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
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| - | <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=5lg0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5lg0 OCA], [http://pdbe.org/5lg0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5lg0 RCSB], [http://www.ebi.ac.uk/pdbsum/5lg0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5lg0 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RN111_HUMAN RN111_HUMAN]] Acts in the NODAL pathway of mesoderm patterning during embryonic development. Acts downstream AXIN1 as an E3 ubiquitin-protein ligase which promotes the ubiquitination of inhibitory SMADs such as SMAD7, induces their proteasomal degradation and thereby enhances the transcriptional activity of TGF-beta and BMP. Activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Associates with UBE2D2 as an E2 enzyme.<ref>PMID:14657019</ref> <ref>PMID:16601693</ref> <ref>PMID:17591695</ref> <ref>PMID:22411132</ref> | + | [https://www.uniprot.org/uniprot/RN111_HUMAN RN111_HUMAN] Acts in the NODAL pathway of mesoderm patterning during embryonic development. Acts downstream AXIN1 as an E3 ubiquitin-protein ligase which promotes the ubiquitination of inhibitory SMADs such as SMAD7, induces their proteasomal degradation and thereby enhances the transcriptional activity of TGF-beta and BMP. Activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Associates with UBE2D2 as an E2 enzyme.<ref>PMID:14657019</ref> <ref>PMID:16601693</ref> <ref>PMID:17591695</ref> <ref>PMID:22411132</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: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Bentrop, D]] | + | [[Category: Bentrop D]] |
| - | [[Category: Birkou, M]] | + | [[Category: Birkou M]] |
| - | [[Category: Chasapis, C T]] | + | [[Category: Chasapis CT]] |
| - | [[Category: Episkopou, V]] | + | [[Category: Episkopou V]] |
| - | [[Category: Herrmann, T]] | + | [[Category: Herrmann T]] |
| - | [[Category: Lelli, M]] | + | [[Category: Lelli M]] |
| - | [[Category: Loutsidou, A K]] | + | [[Category: Loutsidou AK]] |
| - | [[Category: Spyroulias, G A]] | + | [[Category: Spyroulias GA]] |
| - | [[Category: Arkadia]]
| + | |
| - | [[Category: E3 ubiquitin ligase]]
| + | |
| - | [[Category: Ligase]]
| + | |
| - | [[Category: Ring domain]]
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| - | [[Category: Rnf111]]
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| - | [[Category: Tgf-b]]
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| - | [[Category: Tryptophan]]
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| - | [[Category: Ubch5b e2 enzyme]]
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| Structural highlights
Function
RN111_HUMAN Acts in the NODAL pathway of mesoderm patterning during embryonic development. Acts downstream AXIN1 as an E3 ubiquitin-protein ligase which promotes the ubiquitination of inhibitory SMADs such as SMAD7, induces their proteasomal degradation and thereby enhances the transcriptional activity of TGF-beta and BMP. Activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Associates with UBE2D2 as an E2 enzyme.[1] [2] [3] [4]
Publication Abstract from PubMed
Arkadia (Rnf111) is an E3 ubiquitin ligase that plays a central role in the amplification of transforming growth factor beta (TGF-beta) signaling responses by targeting for degradation the negative regulators of the pathway, Smad6 and Smad7, and the nuclear co-repressors Ski and Skil (SnoN). Arkadia's function in vivo depends on the really interesting new gene (RING)-H2 interaction with the E2 enzyme UbcH5b in order to ligate ubiquitin chains on its substrates. A conserved tryptophan (W972) in the C-terminal alpha-helix is widely accepted as essential for E2 recruitment and interaction and thus also for E3 enzymatic activity. The present NMR-driven study provides an atomic-level investigation of the structural and dynamical properties of two W972 Arkadia RING mutants, attempting to illuminate for the first time the differences between a functional and a nonfunctional mutant W972A and W972R, respectively. A TGF-beta-responsive promoter driving luciferase was used to assay for Arkadia function in vivo. These experiments showed that the Arkadia W972A mutant has the same activity as wild-type (WT) Arkadia in enhancing TGF-beta signaling responses, while W972R does not. Only minor structural differences exist between the W972A RING domain and WT-RING. In contrast, the W972R mutant hardly interacts with E2. The loss of function correlates with structural changes in the C-terminal alpha-helix and an increase in the distance between the Zn(II) ions. Our data show that the position occupied by W972 within WT Arkadia is critical for the function of RING and that it depends on the nature of the residue at this position.
A Residue Specific Insight into the Arkadia E3 Ubiquitin Ligase Activity and Conformational Plasticity.,Birkou M, Chasapis CT, Marousis KD, Loutsidou AK, Bentrop D, Lelli M, Herrmann T, Carthy JM, Episkopou V, Spyroulias GA J Mol Biol. 2017 Jul 21;429(15):2373-2386. doi: 10.1016/j.jmb.2017.06.012. Epub, 2017 Jun 22. PMID:28647409[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Koinuma D, Shinozaki M, Komuro A, Goto K, Saitoh M, Hanyu A, Ebina M, Nukiwa T, Miyazawa K, Imamura T, Miyazono K. Arkadia amplifies TGF-beta superfamily signalling through degradation of Smad7. EMBO J. 2003 Dec 15;22(24):6458-70. PMID:14657019 doi:http://dx.doi.org/10.1093/emboj/cdg632
- ↑ Liu W, Rui H, Wang J, Lin S, He Y, Chen M, Li Q, Ye Z, Zhang S, Chan SC, Chen YG, Han J, Lin SC. Axin is a scaffold protein in TGF-beta signaling that promotes degradation of Smad7 by Arkadia. EMBO J. 2006 Apr 19;25(8):1646-58. Epub 2006 Apr 6. PMID:16601693 doi:7601057
- ↑ Levy L, Howell M, Das D, Harkin S, Episkopou V, Hill CS. Arkadia activates Smad3/Smad4-dependent transcription by triggering signal-induced SnoN degradation. Mol Cell Biol. 2007 Sep;27(17):6068-83. Epub 2007 Jun 25. PMID:17591695 doi:http://dx.doi.org/10.1128/MCB.00664-07
- ↑ Chasapis CT, Kandias NG, Episkopou V, Bentrop D, Spyroulias GA. NMR-based insights into the conformational and interaction properties of Arkadia RING-H2 E3 Ub ligase. Proteins. 2012 May;80(5):1484-9. doi: 10.1002/prot.24048. Epub 2012 Mar 13. PMID:22411132 doi:http://dx.doi.org/10.1002/prot.24048
- ↑ Birkou M, Chasapis CT, Marousis KD, Loutsidou AK, Bentrop D, Lelli M, Herrmann T, Carthy JM, Episkopou V, Spyroulias GA. A Residue Specific Insight into the Arkadia E3 Ubiquitin Ligase Activity and Conformational Plasticity. J Mol Biol. 2017 Jul 21;429(15):2373-2386. doi: 10.1016/j.jmb.2017.06.012. Epub, 2017 Jun 22. PMID:28647409 doi:http://dx.doi.org/10.1016/j.jmb.2017.06.012
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