2y6e: Difference between revisions

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-==Ubiquitin Specific Protease 4 is inhibited by its Ubiquitin-like domain==
-<StructureSection load='2y6e' size='340' side='right' caption='[[2y6e]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+==Structure of the D1D2 domain of USP4, the conserved catalytic domain==
+<StructureSection load='2y6e' size='340' side='right'caption='[[2y6e]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2y6e]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y6E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Y6E FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2y6e]] is a 6 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=2Y6E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Y6E FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <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]] 2.4&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=2y6e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y6e OCA], [https://pdbe.org/2y6e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2y6e RCSB], [https://www.ebi.ac.uk/pdbsum/2y6e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2y6e 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=2y6e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y6e OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2y6e RCSB], [http://www.ebi.ac.uk/pdbsum/2y6e PDBsum]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/UBP4_HUMAN UBP4_HUMAN] Hydrolase that deubiquitinates target proteins such as the receptor ADORA2A, PDPK1 and TRIM21. Deubiquitination of ADORA2A increases the amount of functional receptor at the cell surface. Plays a role in the regulation of quality control in the ER.<ref>PMID:7784062</ref> <ref>PMID:16316627</ref> <ref>PMID:16472766</ref> <ref>PMID:16339847</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
-USP4 is a member of the ubiquitin-specific protease (USP) family of deubiquitinating enzymes that has a role in spliceosome regulation. Here, we show that the crystal structure of the minimal catalytic domain of USP4 has the conserved USP-like fold with its typical ubiquitin-binding site. A ubiquitin-like (Ubl) domain inserted into the catalytic domain has autoregulatory function. This Ubl domain can bind to the catalytic domain and compete with the ubiquitin substrate, partially inhibiting USP4 activity against different substrates. Interestingly, other USPs, such as USP39, could relieve this inhibition.
+Ubiquitin-specific protease USP4 is emerging as an important regulator of cellular pathways, including the TGF-beta response, NF-kappaB signalling and splicing, with possible roles in cancer. Here we show that USP4 has its catalytic triad arranged in a productive conformation. Nevertheless, it requires its N-terminal DUSP-Ubl domain to achieve full catalytic turnover. Pre-steady-state kinetics measurements reveal that USP4 catalytic domain activity is strongly inhibited by slow dissociation of ubiquitin after substrate hydrolysis. The DUSP-Ubl domain is able to enhance ubiquitin dissociation, hence promoting efficient turnover. In a mechanism that requires all USP4 domains, binding of the DUSP-Ubl domain promotes a change of a switching loop near the active site. This 'allosteric regulation of product discharge' provides a novel way of regulating deubiquitinating enzymes that may have relevance for other enzyme classes.
-Ubiquitin-specific protease 4 is inhibited by its ubiquitin-like domain.,Luna-Vargas MP, Faesen AC, van Dijk WJ, Rape M, Fish A, Sixma TK EMBO Rep. 2011 Apr 1;12(4):365-72. Epub 2011 Mar 18. PMID:21415856<ref>PMID:21415856</ref>
+The DUSP-Ubl domain of USP4 enhances its catalytic efficiency by promoting ubiquitin exchange.,Clerici M, Luna-Vargas MP, Faesen AC, Sixma TK Nat Commun. 2014 Nov 18;5:5399. doi: 10.1038/ncomms6399. PMID:25404403<ref>PMID:25404403</ref>
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2y6e" style="background-color:#fffaf0;"></div>
 ==See Also==
-*[[Thioesterase|Thioesterase]]
+*[[Thioesterase 3D structures|Thioesterase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Ubiquitin thiolesterase]]
+[[Category: Large Structures]]
-[[Category: Dijk, W J.van.]]
+[[Category: Faesen AC]]
-[[Category: Faesen, A C.]]
+[[Category: Fish A]]
-[[Category: Fish, A.]]
+[[Category: Luna-Vargas MPA]]
-[[Category: Luna-Vargas, M P.A.]]
+[[Category: Rape M]]
-[[Category: Rape, M.]]
+[[Category: Sixma TK]]
-[[Category: Sixma, T K.]]
+[[Category: Van Dijk WJ]]
-[[Category: Hydrolase]]