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| - | [[Image:1w6v.gif|left|200px]]<br /> | |
| - | <applet load="1w6v" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1w6v" /> | |
| - | '''SOLUTION STRUCTURE OF THE DUSP DOMAIN OF HUSP15'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Solution structure of the DUSP domain of hUSP15== |
| - | Ubiquitin-specific proteases (USPs) can remove covalently attached, ubiquitin moieties from target proteins and regulate both the stability, and ubiquitin-signaling state of their substrates. All USPs contain a, conserved catalytic domain surrounded by one or more subdomains, some of, which contribute to target recognition. One such specific subdomain, the, DUSP domain (domain present in ubiquitin-specific proteases), is present, in at least seven different human USPs that regulate the stability of or, interact with the hypoxia-inducible transcription factor HIF1-alpha, the, Von Hippel-Lindau protein (pVHL), cullin E3 ligases, and BRCA2. We, describe the NMR solution structure of the DUSP domain of human USP15, recently implicated in COP9 (constitutive photomorphogenic gene, 9)-signalosome regulation. Its tripod-like structure consists of a 3-fold, alpha-helical bundle supporting a triple-stranded anti-parallel, beta-sheet. The DUSP domain displays a novel fold, an alpha/beta tripod, (AB3). DUSP domain surface properties and previously described work, suggest a potential role in protein/protein interaction or substrate, recognition. | + | <StructureSection load='1w6v' size='340' side='right'caption='[[1w6v]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1w6v]] is a 1 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=1W6V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1W6V FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</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=1w6v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1w6v OCA], [https://pdbe.org/1w6v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1w6v RCSB], [https://www.ebi.ac.uk/pdbsum/1w6v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1w6v ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/UBP15_HUMAN UBP15_HUMAN] Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling and NF-kappa-B pathways. Acts as a key regulator of TGF-beta receptor signaling pathway, but the precise mechanism is still unclear: according to a report, acts by promoting deubiquitination of monoubiquitinated R-SMADs (SMAD1, SMAD2 and/or SMAD3), thereby alleviating inhibition of R-SMADs and promoting activation of TGF-beta target genes (PubMed:21947082). According to another reports, regulates the TGF-beta receptor signaling pathway by mediating deubiquitination and stabilization of TGFBR1, leading to an enhanced TGF-beta signal (PubMed:22344298). Able to mediate deubiquitination of monoubiquitinated substrates as well as 'Lys-48'-linked polyubiquitin chains, protecting them against proteasomal degradation. Acts as an associated component of COP9 signalosome complex (CSN) and regulates different pathways via this association: regulates NF-kappa-B by mediating deubiquitination of NFKBIA and deubiquitinates substrates bound to VCP. Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway.<ref>PMID:16005295</ref> <ref>PMID:17318178</ref> <ref>PMID:19826004</ref> <ref>PMID:19576224</ref> <ref>PMID:19553310</ref> <ref>PMID:21947082</ref> <ref>PMID:22344298</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/w6/1w6v_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </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/main_output.php?pdb_ID=1w6v ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Ubiquitin-specific proteases (USPs) can remove covalently attached ubiquitin moieties from target proteins and regulate both the stability and ubiquitin-signaling state of their substrates. All USPs contain a conserved catalytic domain surrounded by one or more subdomains, some of which contribute to target recognition. One such specific subdomain, the DUSP domain (domain present in ubiquitin-specific proteases), is present in at least seven different human USPs that regulate the stability of or interact with the hypoxia-inducible transcription factor HIF1-alpha, the Von Hippel-Lindau protein (pVHL), cullin E3 ligases, and BRCA2. We describe the NMR solution structure of the DUSP domain of human USP15, recently implicated in COP9 (constitutive photomorphogenic gene 9)-signalosome regulation. Its tripod-like structure consists of a 3-fold alpha-helical bundle supporting a triple-stranded anti-parallel beta-sheet. The DUSP domain displays a novel fold, an alpha/beta tripod (AB3). DUSP domain surface properties and previously described work suggest a potential role in protein/protein interaction or substrate recognition. |
| | | | |
| - | ==About this Structure==
| + | Solution structure of the human ubiquitin-specific protease 15 DUSP domain.,de Jong RN, Ab E, Diercks T, Truffault V, Daniels M, Kaptein R, Folkers GE J Biol Chem. 2006 Feb 24;281(8):5026-31. Epub 2005 Nov 18. PMID:16298993<ref>PMID:16298993</ref> |
| - | 1W6V is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1W6V OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Solution structure of the human ubiquitin-specific protease 15 DUSP domain., de Jong RN, Ab E, Diercks T, Truffault V, Daniels M, Kaptein R, Folkers GE, J Biol Chem. 2006 Feb 24;281(8):5026-31. Epub 2005 Nov 18. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16298993 16298993]
| + | </div> |
| - | [[Category: Homo sapiens]]
| + | <div class="pdbe-citations 1w6v" style="background-color:#fffaf0;"></div> |
| - | [[Category: Single protein]]
| + | |
| - | [[Category: Ubiquitin thiolesterase]]
| + | |
| - | [[Category: Ab, E.]]
| + | |
| - | [[Category: Daniels, M.]]
| + | |
| - | [[Category: Diercks, T.]]
| + | |
| - | [[Category: Folkers, G.E.]]
| + | |
| - | [[Category: Jong, R.D.De.]]
| + | |
| - | [[Category: Kaptein, R.]]
| + | |
| - | [[Category: SPINE, Structural.Proteomics.in.Europe.]]
| + | |
| - | [[Category: Truffault, V.]]
| + | |
| - | [[Category: cleavage]]
| + | |
| - | [[Category: deubiquitinating enzyme]]
| + | |
| - | [[Category: deubiquitylation]]
| + | |
| - | [[Category: dub]]
| + | |
| - | [[Category: dub15]]
| + | |
| - | [[Category: dusp]]
| + | |
| - | [[Category: endopeptidase]]
| + | |
| - | [[Category: spine]]
| + | |
| - | [[Category: structural genomics]]
| + | |
| - | [[Category: structural proteomics in europe]]
| + | |
| - | [[Category: thiolesterase]]
| + | |
| - | [[Category: ubiquitin]]
| + | |
| - | [[Category: ubiquitin carboxyterminal hydrolase]]
| + | |
| - | [[Category: ubiquitin specific protease]]
| + | |
| - | [[Category: ubp15]]
| + | |
| - | [[Category: uch]]
| + | |
| - | [[Category: usp]]
| + | |
| - | [[Category: usp15]]
| + | |
| | | | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:47:12 2007''
| + | ==See Also== |
| | + | *[[Thioesterase 3D structures|Thioesterase 3D structures]] |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | + | [[Category: Homo sapiens]] |
| | + | [[Category: Large Structures]] |
| | + | [[Category: Ab E]] |
| | + | [[Category: Daniels M]] |
| | + | [[Category: De Jong RD]] |
| | + | [[Category: Diercks T]] |
| | + | [[Category: Folkers GE]] |
| | + | [[Category: Kaptein R]] |
| | + | [[Category: Truffault V]] |
| Structural highlights
Function
UBP15_HUMAN Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling and NF-kappa-B pathways. Acts as a key regulator of TGF-beta receptor signaling pathway, but the precise mechanism is still unclear: according to a report, acts by promoting deubiquitination of monoubiquitinated R-SMADs (SMAD1, SMAD2 and/or SMAD3), thereby alleviating inhibition of R-SMADs and promoting activation of TGF-beta target genes (PubMed:21947082). According to another reports, regulates the TGF-beta receptor signaling pathway by mediating deubiquitination and stabilization of TGFBR1, leading to an enhanced TGF-beta signal (PubMed:22344298). Able to mediate deubiquitination of monoubiquitinated substrates as well as 'Lys-48'-linked polyubiquitin chains, protecting them against proteasomal degradation. Acts as an associated component of COP9 signalosome complex (CSN) and regulates different pathways via this association: regulates NF-kappa-B by mediating deubiquitination of NFKBIA and deubiquitinates substrates bound to VCP. Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway.[1] [2] [3] [4] [5] [6] [7]
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
Ubiquitin-specific proteases (USPs) can remove covalently attached ubiquitin moieties from target proteins and regulate both the stability and ubiquitin-signaling state of their substrates. All USPs contain a conserved catalytic domain surrounded by one or more subdomains, some of which contribute to target recognition. One such specific subdomain, the DUSP domain (domain present in ubiquitin-specific proteases), is present in at least seven different human USPs that regulate the stability of or interact with the hypoxia-inducible transcription factor HIF1-alpha, the Von Hippel-Lindau protein (pVHL), cullin E3 ligases, and BRCA2. We describe the NMR solution structure of the DUSP domain of human USP15, recently implicated in COP9 (constitutive photomorphogenic gene 9)-signalosome regulation. Its tripod-like structure consists of a 3-fold alpha-helical bundle supporting a triple-stranded anti-parallel beta-sheet. The DUSP domain displays a novel fold, an alpha/beta tripod (AB3). DUSP domain surface properties and previously described work suggest a potential role in protein/protein interaction or substrate recognition.
Solution structure of the human ubiquitin-specific protease 15 DUSP domain.,de Jong RN, Ab E, Diercks T, Truffault V, Daniels M, Kaptein R, Folkers GE J Biol Chem. 2006 Feb 24;281(8):5026-31. Epub 2005 Nov 18. PMID:16298993[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Hetfeld BK, Helfrich A, Kapelari B, Scheel H, Hofmann K, Guterman A, Glickman M, Schade R, Kloetzel PM, Dubiel W. The zinc finger of the CSN-associated deubiquitinating enzyme USP15 is essential to rescue the E3 ligase Rbx1. Curr Biol. 2005 Jul 12;15(13):1217-21. PMID:16005295 doi:10.1016/j.cub.2005.05.059
- ↑ Schweitzer K, Bozko PM, Dubiel W, Naumann M. CSN controls NF-kappaB by deubiquitinylation of IkappaBalpha. EMBO J. 2007 Mar 21;26(6):1532-41. Epub 2007 Feb 22. PMID:17318178 doi:10.1038/sj.emboj.7601600
- ↑ Cayli S, Klug J, Chapiro J, Frohlich S, Krasteva G, Orel L, Meinhardt A. COP9 signalosome interacts ATP-dependently with p97/valosin-containing protein (VCP) and controls the ubiquitination status of proteins bound to p97/VCP. J Biol Chem. 2009 Dec 11;284(50):34944-53. Epub 2009 Oct 13. PMID:19826004 doi:M109.037952
- ↑ Huang X, Langelotz C, Hetfeld-Pechoc BK, Schwenk W, Dubiel W. The COP9 signalosome mediates beta-catenin degradation by deneddylation and blocks adenomatous polyposis coli destruction via USP15. J Mol Biol. 2009 Aug 28;391(4):691-702. Epub 2009 Jul 1. PMID:19576224 doi:S0022-2836(09)00798-0
- ↑ Vos RM, Altreuter J, White EA, Howley PM. The ubiquitin-specific peptidase USP15 regulates human papillomavirus type 16 E6 protein stability. J Virol. 2009 Sep;83(17):8885-92. doi: 10.1128/JVI.00605-09. Epub 2009 Jun 24. PMID:19553310 doi:10.1128/JVI.00605-09
- ↑ Inui M, Manfrin A, Mamidi A, Martello G, Morsut L, Soligo S, Enzo E, Moro S, Polo S, Dupont S, Cordenonsi M, Piccolo S. USP15 is a deubiquitylating enzyme for receptor-activated SMADs. Nat Cell Biol. 2011 Sep 25;13(11):1368-75. doi: 10.1038/ncb2346. PMID:21947082 doi:10.1038/ncb2346
- ↑ Eichhorn PJ, Rodon L, Gonzalez-Junca A, Dirac A, Gili M, Martinez-Saez E, Aura C, Barba I, Peg V, Prat A, Cuartas I, Jimenez J, Garcia-Dorado D, Sahuquillo J, Bernards R, Baselga J, Seoane J. USP15 stabilizes TGF-beta receptor I and promotes oncogenesis through the activation of TGF-beta signaling in glioblastoma. Nat Med. 2012 Feb 19;18(3):429-35. doi: 10.1038/nm.2619. PMID:22344298 doi:10.1038/nm.2619
- ↑ de Jong RN, Ab E, Diercks T, Truffault V, Daniels M, Kaptein R, Folkers GE. Solution structure of the human ubiquitin-specific protease 15 DUSP domain. J Biol Chem. 2006 Feb 24;281(8):5026-31. Epub 2005 Nov 18. PMID:16298993 doi:10.1074/jbc.M510993200
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