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| | ==The catalytic domain of USP8 in complex with a USP8 specific inhibitor== | | ==The catalytic domain of USP8 in complex with a USP8 specific inhibitor== |
| - | <StructureSection load='3n3k' size='340' side='right' caption='[[3n3k]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='3n3k' size='340' side='right'caption='[[3n3k]], [[Resolution|resolution]] 2.60Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3n3k]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3N3K OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3N3K FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3n3k]] is a 2 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=3N3K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3N3K 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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.6Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2gfo|2gfo]], [[2a9u|2a9u]], [[1whb|1whb]], [[2fzp|2fzp]]</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KIAA0055, UBPY, USP8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens]), RPS27A, UBA52, UBA80, UBB, UBC, UBCEP1, UBCEP2, UBQ ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3n3k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n3k OCA], [https://pdbe.org/3n3k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3n3k RCSB], [https://www.ebi.ac.uk/pdbsum/3n3k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3n3k ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ubiquitin_thiolesterase Ubiquitin thiolesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.2.15 3.1.2.15] </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=3n3k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3n3k OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3n3k RCSB], [http://www.ebi.ac.uk/pdbsum/3n3k PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UBP8_HUMAN UBP8_HUMAN]] Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1.<ref>PMID:9628861</ref> <ref>PMID:16520378</ref> <ref>PMID:17711858</ref> <ref>PMID:18329369</ref> | + | [https://www.uniprot.org/uniprot/UBP8_HUMAN UBP8_HUMAN] Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1.<ref>PMID:9628861</ref> <ref>PMID:16520378</ref> <ref>PMID:17711858</ref> <ref>PMID:18329369</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
| | Check<jmol> | | Check<jmol> |
| | <jmolCheckbox> | | <jmolCheckbox> |
| - | <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/n3/3n3k_consurf.spt"</scriptWhenChecked> | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/n3/3n3k_consurf.spt"</scriptWhenChecked> |
| | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
| - | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf]. | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3n3k ConSurf]. |
| | <div style="clear:both"></div> | | <div style="clear:both"></div> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
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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 3n3k" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Thioesterase|Thioesterase]] | + | *[[Thioesterase 3D structures|Thioesterase 3D structures]] |
| - | *[[Ubiquitin|Ubiquitin]] | + | *[[3D structures of ubiquitin|3D structures of ubiquitin]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Ubiquitin thiolesterase]] | + | [[Category: Large Structures]] |
| - | [[Category: Allali-Hassani, A]] | + | [[Category: Allali-Hassani A]] |
| - | [[Category: Arrowsmith, C H]] | + | [[Category: Arrowsmith CH]] |
| - | [[Category: Avvakumov, G V]] | + | [[Category: Avvakumov GV]] |
| - | [[Category: Bochkarev, A]] | + | [[Category: Bochkarev A]] |
| - | [[Category: Bountra, C]] | + | [[Category: Bountra C]] |
| | + | [[Category: Dhe-Paganon S]] |
| | + | [[Category: Edwards AM]] |
| | + | [[Category: Ernst A]] |
| | + | [[Category: Lam R]] |
| | + | [[Category: Li Y]] |
| | + | [[Category: Sidhu S]] |
| | [[Category: Structural genomic]] | | [[Category: Structural genomic]] |
| - | [[Category: Dhe-Paganon, S]]
| + | [[Category: Walker JR]] |
| - | [[Category: Edwards, A M]]
| + | [[Category: Weigelt J]] |
| - | [[Category: Ernst, A]]
| + | [[Category: Xue S]] |
| - | [[Category: Lam, R]]
| + | |
| - | [[Category: Li, Y]]
| + | |
| - | [[Category: Sidhu, S]]
| + | |
| - | [[Category: Walker, J R]] | + | |
| - | [[Category: Weigelt, J]] | + | |
| - | [[Category: Xue, S]] | + | |
| - | [[Category: Deubiquitinating enzyme]]
| + | |
| - | [[Category: Dub]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: Isopeptide bond]]
| + | |
| - | [[Category: Nucleus]]
| + | |
| - | [[Category: Phosphoprotein]]
| + | |
| - | [[Category: Protease]]
| + | |
| - | [[Category: Sgc]]
| + | |
| - | [[Category: Thiol protease]]
| + | |
| - | [[Category: Ubiquitin]]
| + | |
| - | [[Category: Ubl conjugation pathway]]
| + | |
| - | [[Category: Zinc ribbon]]
| + | |
| Structural highlights
Function
UBP8_HUMAN Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation. Converts both 'Lys-48' an 'Lys-63'-linked ubiquitin chains. Catalytic activity is enhanced in the M phase. Involved in cell proliferation. Required to enter into S phase in response to serum stimulation. May regulate T-cell anergy mediated by RNF128 via the formation of a complex containing RNF128 and OTUB1. Probably regulates the stability of STAM2 and RASGRF1. Regulates endosomal ubiquitin dynamics, cargo sorting, membrane traffic at early endosomes, and maintenance of ESCRT-0 stability. The level of protein ubiquitination on endosomes is essential for maintaining the morphology of the organelle. Deubiquitinates EPS15 and controles tyrosine kinase stability. Removes conjugated ubiquitin from EGFR thus regulating EGFR degradation and downstream MAPK signaling. Involved in acrosome biogenesis through interaction with the spermatid ESCRT-0 complex and microtubules. Deubiquitinates BIRC6/bruce and KIF23/MKLP1.[1] [2] [3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The ubiquitin system regulates virtually all aspects of cellular function. We report a method to target the myriad enzymes that govern ubiquitination of protein substrates. We used massively diverse combinatorial libraries of ubiquitin variants to develop inhibitors of four deubiquitinases (DUBs) and analyzed the DUB-inhibitor complexes with crystallography. We extended the selection strategy to the ubiquitin conjugating (E2) and ubiquitin ligase (E3) enzymes and found that ubiquitin variants can also enhance enzyme activity. Last, we showed that ubiquitin variants can bind selectively to ubiquitin-binding domains. Ubiquitin variants exhibit selective function in cells and thus enable orthogonal modulation of specific enzymatic steps in the ubiquitin system.
A strategy for modulation of enzymes in the ubiquitin system.,Ernst A, Avvakumov G, Tong J, Fan Y, Zhao Y, Alberts P, Persaud A, Walker JR, Neculai AM, Neculai D, Vorobyov A, Garg P, Beatty L, Chan PK, Juang YC, Landry MC, Yeh C, Zeqiraj E, Karamboulas K, Allali-Hassani A, Vedadi M, Tyers M, Moffat J, Sicheri F, Pelletier L, Durocher D, Raught B, Rotin D, Yang J, Moran MF, Dhe-Paganon S, Sidhu SS Science. 2013 Feb 1;339(6119):590-5. doi: 10.1126/science.1230161. Epub 2013 Jan , 3. PMID:23287719[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Naviglio S, Mattecucci C, Matoskova B, Nagase T, Nomura N, Di Fiore PP, Draetta GF. UBPY: a growth-regulated human ubiquitin isopeptidase. EMBO J. 1998 Jun 15;17(12):3241-50. PMID:9628861 doi:http://dx.doi.org/10.1093/emboj/17.12.3241
- ↑ Row PE, Prior IA, McCullough J, Clague MJ, Urbe S. The ubiquitin isopeptidase UBPY regulates endosomal ubiquitin dynamics and is essential for receptor down-regulation. J Biol Chem. 2006 May 5;281(18):12618-24. Epub 2006 Mar 6. PMID:16520378 doi:http://dx.doi.org/10.1074/jbc.M512615200
- ↑ Row PE, Liu H, Hayes S, Welchman R, Charalabous P, Hofmann K, Clague MJ, Sanderson CM, Urbe S. The MIT domain of UBPY constitutes a CHMP binding and endosomal localization signal required for efficient epidermal growth factor receptor degradation. J Biol Chem. 2007 Oct 19;282(42):30929-37. Epub 2007 Aug 21. PMID:17711858 doi:http://dx.doi.org/10.1074/jbc.M704009200
- ↑ Pohl C, Jentsch S. Final stages of cytokinesis and midbody ring formation are controlled by BRUCE. Cell. 2008 Mar 7;132(5):832-45. doi: 10.1016/j.cell.2008.01.012. PMID:18329369 doi:http://dx.doi.org/10.1016/j.cell.2008.01.012
- ↑ Ernst A, Avvakumov G, Tong J, Fan Y, Zhao Y, Alberts P, Persaud A, Walker JR, Neculai AM, Neculai D, Vorobyov A, Garg P, Beatty L, Chan PK, Juang YC, Landry MC, Yeh C, Zeqiraj E, Karamboulas K, Allali-Hassani A, Vedadi M, Tyers M, Moffat J, Sicheri F, Pelletier L, Durocher D, Raught B, Rotin D, Yang J, Moran MF, Dhe-Paganon S, Sidhu SS. A strategy for modulation of enzymes in the ubiquitin system. Science. 2013 Feb 1;339(6119):590-5. doi: 10.1126/science.1230161. Epub 2013 Jan , 3. PMID:23287719 doi:10.1126/science.1230161
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