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| | <StructureSection load='5l8e' size='340' side='right'caption='[[5l8e]], [[Resolution|resolution]] 2.30Å' scene=''> | | <StructureSection load='5l8e' size='340' side='right'caption='[[5l8e]], [[Resolution|resolution]] 2.30Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5l8e]] is a 3 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=5L8E OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5L8E FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5l8e]] is a 3 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=5L8E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5L8E FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</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]] 2.3Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=UNK:UNKNOWN'>UNK</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">WDR48, KIAA1449, UAF1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5l8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l8e OCA], [https://pdbe.org/5l8e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5l8e RCSB], [https://www.ebi.ac.uk/pdbsum/5l8e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5l8e ProSAT]</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=5l8e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5l8e OCA], [http://pdbe.org/5l8e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5l8e RCSB], [http://www.ebi.ac.uk/pdbsum/5l8e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5l8e ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/WDR48_HUMAN WDR48_HUMAN]] Autosomal recessive spastic paraplegia type 60. | + | [https://www.uniprot.org/uniprot/WDR48_HUMAN WDR48_HUMAN] Autosomal recessive spastic paraplegia type 60. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/WDR48_HUMAN WDR48_HUMAN]] Regulator of deubiquitinating complexes. Acts as a strong activator of USP1 by enhancing the USP1-mediated deubiquitination of FANCD2; USP1 being almost inactive by itself. Also activates deubiquitinating activity of complexes containing USP12 and USP46, respectively. Activates deubiquitination by increasing the catalytic turnover without increasing the affinity of deubiquitinating enzymes for the substrate. In case of infection by Herpesvirus saimiri, may play a role in vesicular transport or membrane fusion events necessary for transport to lysosomes. Induces lysosomal vesicle formation via interaction with Herpesvirus saimiri tyrosine kinase-interacting protein (TIP). Subsequently, TIP recruits tyrosine-protein kinase LCK, resulting in down-regulation of T-cell antigen receptor TCR. May play a role in generation of enlarged endosomal vesicles via interaction with TIP. In case of infection by papillomavirus HPV11, promotes the maintenance of the viral genome via its interaction with HPV11 helicase E1.<ref>PMID:12196293</ref> <ref>PMID:18082604</ref> <ref>PMID:19075014</ref> | + | [https://www.uniprot.org/uniprot/WDR48_HUMAN WDR48_HUMAN] Regulator of deubiquitinating complexes. Acts as a strong activator of USP1 by enhancing the USP1-mediated deubiquitination of FANCD2; USP1 being almost inactive by itself. Also activates deubiquitinating activity of complexes containing USP12 and USP46, respectively. Activates deubiquitination by increasing the catalytic turnover without increasing the affinity of deubiquitinating enzymes for the substrate. In case of infection by Herpesvirus saimiri, may play a role in vesicular transport or membrane fusion events necessary for transport to lysosomes. Induces lysosomal vesicle formation via interaction with Herpesvirus saimiri tyrosine kinase-interacting protein (TIP). Subsequently, TIP recruits tyrosine-protein kinase LCK, resulting in down-regulation of T-cell antigen receptor TCR. May play a role in generation of enlarged endosomal vesicles via interaction with TIP. In case of infection by papillomavirus HPV11, promotes the maintenance of the viral genome via its interaction with HPV11 helicase E1.<ref>PMID:12196293</ref> <ref>PMID:18082604</ref> <ref>PMID:19075014</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Dharadhar, S]] | + | [[Category: Dharadhar S]] |
| - | [[Category: Sixma, T]] | + | [[Category: Sixma T]] |
| - | [[Category: Structural protein]]
| + | |
| - | [[Category: Wdr48 activates usp1/12/46 b propellar]]
| + | |
| Structural highlights
Disease
WDR48_HUMAN Autosomal recessive spastic paraplegia type 60.
Function
WDR48_HUMAN Regulator of deubiquitinating complexes. Acts as a strong activator of USP1 by enhancing the USP1-mediated deubiquitination of FANCD2; USP1 being almost inactive by itself. Also activates deubiquitinating activity of complexes containing USP12 and USP46, respectively. Activates deubiquitination by increasing the catalytic turnover without increasing the affinity of deubiquitinating enzymes for the substrate. In case of infection by Herpesvirus saimiri, may play a role in vesicular transport or membrane fusion events necessary for transport to lysosomes. Induces lysosomal vesicle formation via interaction with Herpesvirus saimiri tyrosine kinase-interacting protein (TIP). Subsequently, TIP recruits tyrosine-protein kinase LCK, resulting in down-regulation of T-cell antigen receptor TCR. May play a role in generation of enlarged endosomal vesicles via interaction with TIP. In case of infection by papillomavirus HPV11, promotes the maintenance of the viral genome via its interaction with HPV11 helicase E1.[1] [2] [3]
Publication Abstract from PubMed
Regulation of deubiquitinating enzyme (DUB) activity is an essential step for proper function of cellular ubiquitin signals. UAF1 is a WD40 repeat protein, which binds and activates three important DUBs, USP1, USP12 and USP46. Here, we report the crystal structure of the USP12-Ub/UAF1 complex at a resolution of 2.8A and of UAF1 at 2.3A. In the complex we find two potential sites for UAF1 binding, analogous to what was seen in a USP46/UAF1 complex. In line with these observed dual binding states, we show here that USP12/UAF1 complex has 1:2 stoichiometry in solution, with a two-step binding at 4nM and 325nM respectively. Mutagenesis studies show that the fingers sub-domain of USP12 interacts with UAF1 to form the high affinity interface. Our activation studies confirm that the high affinity binding is important for activation while the second UAF1 binding does not affect activation. Nevertheless, we show that this two step binding is conserved in the well-studied USP12 paralog, USP1. Our results highlight the interfaces essential for regulation of USP12 activity and show a conserved second binding of UAF1 which could be important for regulatory functions independent of USP12 activity.
A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme.,Dharadhar S, Clerici M, van Dijk WJ, Fish A, Sixma TK J Struct Biol. 2016 Sep 17. pii: S1047-8477(16)30200-3. doi:, 10.1016/j.jsb.2016.09.011. PMID:27650958[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Park J, Lee BS, Choi JK, Means RE, Choe J, Jung JU. Herpesviral protein targets a cellular WD repeat endosomal protein to downregulate T lymphocyte receptor expression. Immunity. 2002 Aug;17(2):221-33. PMID:12196293
- ↑ Cohn MA, Kowal P, Yang K, Haas W, Huang TT, Gygi SP, D'Andrea AD. A UAF1-containing multisubunit protein complex regulates the Fanconi anemia pathway. Mol Cell. 2007 Dec 14;28(5):786-97. PMID:18082604 doi:http://dx.doi.org/10.1016/j.molcel.2007.09.031
- ↑ Cohn MA, Kee Y, Haas W, Gygi SP, D'Andrea AD. UAF1 is a subunit of multiple deubiquitinating enzyme complexes. J Biol Chem. 2009 Feb 20;284(8):5343-51. doi: 10.1074/jbc.M808430200. Epub 2008, Dec 15. PMID:19075014 doi:http://dx.doi.org/10.1074/jbc.M808430200
- ↑ Dharadhar S, Clerici M, van Dijk WJ, Fish A, Sixma TK. A conserved two-step binding for the UAF1 regulator to the USP12 deubiquitinating enzyme. J Struct Biol. 2016 Sep 17. pii: S1047-8477(16)30200-3. doi:, 10.1016/j.jsb.2016.09.011. PMID:27650958 doi:http://dx.doi.org/10.1016/j.jsb.2016.09.011
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