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| | <StructureSection load='6h4i' size='340' side='right'caption='[[6h4i]], [[Resolution|resolution]] 3.22Å' scene=''> | | <StructureSection load='6h4i' size='340' side='right'caption='[[6h4i]], [[Resolution|resolution]] 3.22Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6h4i]] is a 2 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=6H4I OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6H4I FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6h4i]] 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=6H4I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6H4I 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></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]] 3.22Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6h4h|6h4h]]</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=6h4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h4i OCA], [https://pdbe.org/6h4i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6h4i RCSB], [https://www.ebi.ac.uk/pdbsum/6h4i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6h4i ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">USP28, KIAA1515 ([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/Ubiquitinyl_hydrolase_1 Ubiquitinyl hydrolase 1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.19.12 3.4.19.12] </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=6h4i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6h4i OCA], [http://pdbe.org/6h4i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6h4i RCSB], [http://www.ebi.ac.uk/pdbsum/6h4i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6h4i ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UBP28_HUMAN UBP28_HUMAN]] Deubiquitinase involved in DNA damage response checkpoint and MYC proto-oncogene stability. Involved in DNA damage induced apoptosis by specifically deubiquitinating proteins of the DNA damage pathway such as CLSPN. Also involved in G2 DNA damage checkpoint, by deubiquitinating CLSPN, and preventing its degradation by the anaphase promoting complex/cyclosome (APC/C). In contrast, it does not deubiquitinate PLK1. Specifically deubiquitinates MYC in the nucleoplasm, leading to prevent MYC degradation by the proteasome: acts by specifically interacting with isoform 1 of FBXW7 (FBW7alpha) in the nucleoplasm and counteracting ubiquitination of MYC by the SCF(FBW7) complex. In contrast, it does not interact with isoform 4 of FBXW7 (FBW7gamma) in the nucleolus, allowing MYC degradation and explaining the selective MYC degradation in the nucleolus.<ref>PMID:16901786</ref> <ref>PMID:17558397</ref> <ref>PMID:17873522</ref> <ref>PMID:18662541</ref> | + | [https://www.uniprot.org/uniprot/UBP28_HUMAN UBP28_HUMAN] Deubiquitinase involved in DNA damage response checkpoint and MYC proto-oncogene stability. Involved in DNA damage induced apoptosis by specifically deubiquitinating proteins of the DNA damage pathway such as CLSPN. Also involved in G2 DNA damage checkpoint, by deubiquitinating CLSPN, and preventing its degradation by the anaphase promoting complex/cyclosome (APC/C). In contrast, it does not deubiquitinate PLK1. Specifically deubiquitinates MYC in the nucleoplasm, leading to prevent MYC degradation by the proteasome: acts by specifically interacting with isoform 1 of FBXW7 (FBW7alpha) in the nucleoplasm and counteracting ubiquitination of MYC by the SCF(FBW7) complex. In contrast, it does not interact with isoform 4 of FBXW7 (FBW7gamma) in the nucleolus, allowing MYC degradation and explaining the selective MYC degradation in the nucleolus.<ref>PMID:16901786</ref> <ref>PMID:17558397</ref> <ref>PMID:17873522</ref> <ref>PMID:18662541</ref> |
| | <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 6h4i" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6h4i" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Thioesterase 3D structures|Thioesterase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Ubiquitinyl hydrolase 1]]
| + | [[Category: Kisker C]] |
| - | [[Category: Kisker, C]] | + | [[Category: Klemm TA]] |
| - | [[Category: Klemm, T A]] | + | [[Category: Sauer F]] |
| - | [[Category: Sauer, F]] | + | |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Deubiquitinase]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Ubiquitin]]
| + | |
| - | [[Category: Usp]]
| + | |
| Structural highlights
Function
UBP28_HUMAN Deubiquitinase involved in DNA damage response checkpoint and MYC proto-oncogene stability. Involved in DNA damage induced apoptosis by specifically deubiquitinating proteins of the DNA damage pathway such as CLSPN. Also involved in G2 DNA damage checkpoint, by deubiquitinating CLSPN, and preventing its degradation by the anaphase promoting complex/cyclosome (APC/C). In contrast, it does not deubiquitinate PLK1. Specifically deubiquitinates MYC in the nucleoplasm, leading to prevent MYC degradation by the proteasome: acts by specifically interacting with isoform 1 of FBXW7 (FBW7alpha) in the nucleoplasm and counteracting ubiquitination of MYC by the SCF(FBW7) complex. In contrast, it does not interact with isoform 4 of FBXW7 (FBW7gamma) in the nucleolus, allowing MYC degradation and explaining the selective MYC degradation in the nucleolus.[1] [2] [3] [4]
Publication Abstract from PubMed
Deubiquitinases have emerged as promising drug targets for cancer therapy. The two DUBs USP25 and USP28 share high similarity but vary in their cellular functions. USP28 is known for its tumor-promoting role, whereas USP25 is a regulator of the innate immune system and, recently, a role in tumorigenesis was proposed. We solved the structures of the catalytic domains of both proteins and established substantial differences in their activities. While USP28 is a constitutively active dimer, USP25 presents an auto-inhibited tetramer. Our data indicate that the activation of USP25 is not achieved through substrate or ubiquitin binding. USP25 cancer-associated mutations lead to activation in vitro and in vivo, thereby providing a functional link between auto-inhibition and the cancer-promoting role of the enzyme. Our work led to the identification of significant differences between USP25 and USP28 and provided the molecular basis for the development of new and highly specific anti-cancer drugs.
Differential Oligomerization of the Deubiquitinases USP25 and USP28 Regulates Their Activities.,Sauer F, Klemm T, Kollampally RB, Tessmer I, Nair RK, Popov N, Kisker C Mol Cell. 2019 Mar 22. pii: S1097-2765(19)30140-6. doi:, 10.1016/j.molcel.2019.02.029. PMID:30926243[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Zhang D, Zaugg K, Mak TW, Elledge SJ. A role for the deubiquitinating enzyme USP28 in control of the DNA-damage response. Cell. 2006 Aug 11;126(3):529-42. PMID:16901786 doi:http://dx.doi.org/10.1016/j.cell.2006.06.039
- ↑ Popov N, Wanzel M, Madiredjo M, Zhang D, Beijersbergen R, Bernards R, Moll R, Elledge SJ, Eilers M. The ubiquitin-specific protease USP28 is required for MYC stability. Nat Cell Biol. 2007 Jul;9(7):765-74. Epub 2007 Jun 10. PMID:17558397 doi:http://dx.doi.org/10.1038/ncb1601
- ↑ Popov N, Herold S, Llamazares M, Schulein C, Eilers M. Fbw7 and Usp28 regulate myc protein stability in response to DNA damage. Cell Cycle. 2007 Oct 1;6(19):2327-31. Epub 2007 Jul 26. PMID:17873522
- ↑ Bassermann F, Frescas D, Guardavaccaro D, Busino L, Peschiaroli A, Pagano M. The Cdc14B-Cdh1-Plk1 axis controls the G2 DNA-damage-response checkpoint. Cell. 2008 Jul 25;134(2):256-67. doi: 10.1016/j.cell.2008.05.043. PMID:18662541 doi:http://dx.doi.org/10.1016/j.cell.2008.05.043
- ↑ Sauer F, Klemm T, Kollampally RB, Tessmer I, Nair RK, Popov N, Kisker C. Differential Oligomerization of the Deubiquitinases USP25 and USP28 Regulates Their Activities. Mol Cell. 2019 Mar 22. pii: S1097-2765(19)30140-6. doi:, 10.1016/j.molcel.2019.02.029. PMID:30926243 doi:http://dx.doi.org/10.1016/j.molcel.2019.02.029
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