|
|
| Line 1: |
Line 1: |
| | | | |
| | ==Solution structure of the fourth WW domain of WWP2 with GB1-tag== | | ==Solution structure of the fourth WW domain of WWP2 with GB1-tag== |
| - | <StructureSection load='6rss' size='340' side='right'caption='[[6rss]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | + | <StructureSection load='6rss' size='340' side='right'caption='[[6rss]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6rss]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6RSS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6RSS FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6rss]] 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=6RSS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6RSS FirstGlance]. <br> |
| - | </td></tr><tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.3.2.26 2.3.2.26] </span></td></tr> | + | </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=6rss FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rss OCA], [https://pdbe.org/6rss PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6rss RCSB], [https://www.ebi.ac.uk/pdbsum/6rss PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6rss ProSAT]</span></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=6rss FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6rss OCA], [http://pdbe.org/6rss PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6rss RCSB], [http://www.ebi.ac.uk/pdbsum/6rss PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6rss ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/WWP2_HUMAN WWP2_HUMAN]] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level. Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation.<ref>PMID:19274063</ref> <ref>PMID:19651900</ref> | + | [https://www.uniprot.org/uniprot/WWP2_HUMAN WWP2_HUMAN] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level. Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation.<ref>PMID:19274063</ref> <ref>PMID:19651900</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 18: |
Line 17: |
| | </div> | | </div> |
| | <div class="pdbe-citations 6rss" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6rss" 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: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Transferase]]
| + | [[Category: Blumenschein TMA]] |
| - | [[Category: Blumenschein, T M.A]] | + | [[Category: Chantry A]] |
| - | [[Category: Chantry, A]] | + | [[Category: Tolchard J]] |
| - | [[Category: Tolchard, J]] | + | [[Category: Wahl LC]] |
| - | [[Category: Wahl, L C]] | + | [[Category: Watt JE]] |
| - | [[Category: Watt, J E]] | + | |
| - | [[Category: E3 ubiquitin ligase]]
| + | |
| - | [[Category: Nedd4]]
| + | |
| - | [[Category: Ppxy motif binding]]
| + | |
| - | [[Category: Protein binding]]
| + | |
| - | [[Category: Three-stranded antiparallel beta-sheet]]
| + | |
| Structural highlights
Function
WWP2_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level. Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation-induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation.[1] [2]
Publication Abstract from PubMed
WWP2 is an E3 ubiquitin ligase that differentially regulates the contextual tumour suppressor/progressor TGFbeta signalling pathway by alternate isoform expression. WWP2 isoforms select signal transducer Smad2/3 or inhibitor Smad7 substrates for degradation through different compositions of protein-protein interaction WW domains. The WW4 domain-containing WWP2-C induces Smad7 turnover in vivo and positively regulates the metastatic epithelial-mesenchymal transition programme. This activity and the overexpression of these isoforms in human cancers make them candidates for therapeutic intervention. Here, we use NMR spectroscopy to solve the solution structure of the WWP2 WW4 domain and observe the binding characteristics of Smad7 substrate peptide. We also reveal that WW4 has an enhanced affinity for a Smad7 peptide phosphorylated at serine 206 adjacent to the PPxY motif. Using the same approach, we show that the WW3 domain also binds Smad7 and has significantly enhanced Smad7 binding affinity when expressed in tandem with the WW4 domain. Furthermore, and relevant to these biophysical findings, we present evidence for a novel WWP2 isoform (WWP2C-DeltaHECT) comprising WW3-WW4 tandem domains and a truncated HECT domain that can inhibit TGFbeta signalling pathway activity, providing a further layer of complexity and feedback to the WWP2 regulatory apparatus. Collectively, our data reveal a structural platform for Smad substrate selection by WWP2 isoform WW domains that may be significant in the context of WWP2 isoform switching linked to tumorigenesis.
Smad7 Binds Differently to Individual and Tandem WW3 and WW4 Domains of WWP2 Ubiquitin Ligase Isoforms.,Wahl LC, Watt JE, Yim HTT, De Bourcier D, Tolchard J, Soond SM, Blumenschein TMA, Chantry A Int J Mol Sci. 2019 Sep 21;20(19). pii: ijms20194682. doi: 10.3390/ijms20194682. PMID:31546607[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Xu H, Wang W, Li C, Yu H, Yang A, Wang B, Jin Y. WWP2 promotes degradation of transcription factor OCT4 in human embryonic stem cells. Cell Res. 2009 May;19(5):561-73. doi: 10.1038/cr.2009.31. PMID:19274063 doi:http://dx.doi.org/10.1038/cr.2009.31
- ↑ Chen A, Gao B, Zhang J, McEwen T, Ye SQ, Zhang D, Fang D. The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination. Mol Cell Biol. 2009 Oct;29(19):5348-56. doi: 10.1128/MCB.00407-09. Epub 2009 Aug , 3. PMID:19651900 doi:http://dx.doi.org/10.1128/MCB.00407-09
- ↑ Wahl LC, Watt JE, Yim HTT, De Bourcier D, Tolchard J, Soond SM, Blumenschein TMA, Chantry A. Smad7 Binds Differently to Individual and Tandem WW3 and WW4 Domains of WWP2 Ubiquitin Ligase Isoforms. Int J Mol Sci. 2019 Sep 21;20(19). pii: ijms20194682. doi: 10.3390/ijms20194682. PMID:31546607 doi:http://dx.doi.org/10.3390/ijms20194682
|
