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| | ==Solution Structure of the RAZUL domain from 26S proteasome subunit hRpn10/S5a complexed with the AZUL domain from E3 ligase E6AP/UBE3A== | | ==Solution Structure of the RAZUL domain from 26S proteasome subunit hRpn10/S5a complexed with the AZUL domain from E3 ligase E6AP/UBE3A== |
| - | <StructureSection load='6u19' size='340' side='right'caption='[[6u19]], [[NMR_Ensembles_of_Models | 15 NMR models]]' scene=''> | + | <StructureSection load='6u19' size='340' side='right'caption='[[6u19]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6u19]] is a 2 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=6U19 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6U19 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6u19]] is a 2 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=6U19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U19 FirstGlance]. <br> |
| | </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> | | </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">[[2kr1|2kr1]]</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=6u19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u19 OCA], [https://pdbe.org/6u19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u19 RCSB], [https://www.ebi.ac.uk/pdbsum/6u19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u19 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PSMD4, MCB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), UBE3A, E6AP, EPVE6AP, HPVE6A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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>
| + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6u19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u19 OCA], [http://pdbe.org/6u19 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6u19 RCSB], [http://www.ebi.ac.uk/pdbsum/6u19 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6u19 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| - | == Disease == | |
| - | [[http://www.uniprot.org/uniprot/UBE3A_HUMAN UBE3A_HUMAN]] Defects in UBE3A are a cause of Angelman syndrome (AS) [MIM:[http://omim.org/entry/105830 105830]]; also known as 'happy puppet syndrome'. AS is characterized by features of severe motor and intellectual retardation, microcephaly, ataxia, frequent jerky limb movements and flapping of the arms and hands, hypotonia, hyperactivity, hypopigmentation, seizures, absence of speech, frequent smiling and episodes of paroxysmal laughter, and an unusual facies characterized by macrostomia, a large mandible and open-mouthed expression, a great propensity for protruding the tongue ('tongue thrusting'), and an occipital groove.<ref>PMID:10508479</ref> <ref>PMID:9585605</ref> | |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PSMD4_HUMAN PSMD4_HUMAN]] Binds and presumably selects ubiquitin-conjugates for destruction. Displays selectivity for longer polyubiquitin chains. Modulates intestinal fluid secretion. [[http://www.uniprot.org/uniprot/UBE3A_HUMAN UBE3A_HUMAN]] E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates. Several substrates have been identified including the RAD23A and RAD23B, MCM7 (which is involved in DNA replication), annexin A1, the PML tumor suppressor, and the cell cycle regulator CDKN1B. Catalyzes the high-risk human papilloma virus E6-mediated ubiquitination of p53/TP53, contributing to the neoplastic progression of cells infected by these viruses. Additionally, may function as a cellular quality control ubiquitin ligase by helping the degradation of the cytoplasmic misfolded proteins. Finally, UBE3A also promotes its own degradation in vivo.<ref>PMID:10373495</ref> <ref>PMID:19325566</ref> <ref>PMID:19233847</ref> <ref>PMID:19204938</ref> <ref>PMID:19591933</ref> <ref>PMID:22645313</ref> | + | [https://www.uniprot.org/uniprot/PSMD4_HUMAN PSMD4_HUMAN] Binds and presumably selects ubiquitin-conjugates for destruction. Displays selectivity for longer polyubiquitin chains. Modulates intestinal fluid secretion. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6u19" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6u19" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Proteasome 3D structures|Proteasome 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Transferase]]
| + | [[Category: Chen X]] |
| - | [[Category: Chen, X]] | + | [[Category: Walters KJ]] |
| - | [[Category: Walters, K J]] | + | |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Proteasome]]
| + | |
| - | [[Category: Structural protein]]
| + | |
| - | [[Category: Subunit]]
| + | |
| - | [[Category: Ubiquitination]]
| + | |
| Structural highlights
Function
PSMD4_HUMAN Binds and presumably selects ubiquitin-conjugates for destruction. Displays selectivity for longer polyubiquitin chains. Modulates intestinal fluid secretion.
Publication Abstract from PubMed
Regulated proteolysis by proteasomes involves ~800 enzymes for substrate modification with ubiquitin, including ~600 E3 ligases. We report here that E6AP/UBE3A is distinguished from other E3 ligases by having a 12 nM binding site at the proteasome contributed by substrate receptor hRpn10/PSMD4/S5a. Intrinsically disordered by itself, and previously uncharacterized, the E6AP-binding domain in hRpn10 locks into a well-defined helical structure to form an intermolecular 4-helix bundle with the E6AP AZUL, which is unique to this E3. We thus name the hRpn10 AZUL-binding domain RAZUL. We further find in human cells that loss of RAZUL by CRISPR-based gene editing leads to loss of E6AP at proteasomes. Moreover, proteasome-associated ubiquitin is reduced following E6AP knockdown or displacement from proteasomes, suggesting that E6AP ubiquitinates substrates at or for the proteasome. Altogether, our findings indicate E6AP to be a privileged E3 for the proteasome, with a dedicated, high affinity binding site contributed by hRpn10.
Structure of E3 ligase E6AP with a proteasome-binding site provided by substrate receptor hRpn10.,Buel GR, Chen X, Chari R, O'Neill MJ, Ebelle DL, Jenkins C, Sridharan V, Tarasov SG, Tarasova NI, Andresson T, Walters KJ Nat Commun. 2020 Mar 10;11(1):1291. doi: 10.1038/s41467-020-15073-7. PMID:32157086[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Buel GR, Chen X, Chari R, O'Neill MJ, Ebelle DL, Jenkins C, Sridharan V, Tarasov SG, Tarasova NI, Andresson T, Walters KJ. Structure of E3 ligase E6AP with a proteasome-binding site provided by substrate receptor hRpn10. Nat Commun. 2020 Mar 10;11(1):1291. doi: 10.1038/s41467-020-15073-7. PMID:32157086 doi:http://dx.doi.org/10.1038/s41467-020-15073-7
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