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2zfy

From Proteopedia

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Current revision

Crystal structure of human Otubain 1

Structural highlights

2zfy is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.69Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

OTUB1_HUMAN Hydrolase that can specifically remove 'Lys-48'-linked conjugated ubiquitin from proteins and plays an important regulatory role at the level of protein turnover by preventing degradation. Regulator of T-cell anergy, a phenomenon that occurs when T-cells are rendered unresponsive to antigen rechallenge and no longer respond to their cognate antigen. Acts via its interaction with RNF128/GRAIL, a crucial inductor of CD4 T-cell anergy. Isoform 1 destabilizes RNF128, leading to prevent anergy. In contrast, isoform 2 stabilizes RNF128 and promotes anergy. Surprisingly, it regulates RNF128-mediated ubiquitination, but does not deubiquitinate polyubiquitinated RNF128. Deubiquitinates estrogen receptor alpha (ESR1). Mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains, but not 'Lys-63'-linked polyubiquitin chains. Not able to cleave di-ubiquitin. Also capable of removing NEDD8 from NEDD8 conjugates, but with a much lower preference compared to 'Lys-48'-linked ubiquitin.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] Plays a key non-catalytic role in DNA repair regulation by inhibiting activity of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites. Inhibits RNF168 independently of ubiquitin thioesterase activity by binding and inhibiting UBE2N/UBC13, the E2 partner of RNF168, thereby limiting spreading of 'Lys-63'-linked histone H2A and H2AX marks. Inhibition occurs by binding to free ubiquitin: free ubiquitin acts as an allosteric regulator that increases affinity for UBE2N/UBC13 and disrupts interaction with UBE2V1. The OTUB1-UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a cleaved 'Lys48'-linked di-ubiquitin chain.^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14]

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

OTUB (otubain) 1 is a human deubiquitinating enzyme that is implicated in mediating lymphocyte antigen responsiveness, but whose molecular function is generally not well defined. A structural analysis of OTUB1 shows differences in accessibility to the active site and in surface properties of the substrate-binding regions when compared with its close homologue, OTUB2, suggesting variations in regulatory mechanisms and substrate specificity. Biochemical analysis reveals that OTUB1 has a preference for cleaving Lys(48)-linked polyubiquitin chains over Lys(63)-linked polyubiquitin chains, and it is capable of cleaving NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8), but not SUMO (small ubiquitin-related modifier) 1/2/3 and ISG15 (interferon-stimulated gene 15) conjugates. A functional comparison of OTUB1 and OTUB2 indicated a differential reactivity towards ubiquitin-based active-site probes carrying a vinyl methyl ester, a 2-chloroethyl or a 2-bromoethyl group at the C-terminus. Mutational analysis suggested that a narrow P1' site, as observed in OTUB1, correlates with its ability to preferentially cleave Lys(48)-linked ubiquitin chains. Analysis of cellular interaction partners of OTUB1 by co-immunoprecipitation and MS/MS (tandem mass spectrometry) experiments demonstrated that FUS [fusion involved in t(12;6) in malignant liposarcoma; also known as TLS (translocation in liposarcoma) or CHOP (CCAAT/enhancer-binding protein homologous protein)] and RACK1 [receptor for activated kinase 1; also known as GNB2L1 (guanine-nucleotide-binding protein beta polypeptide 2-like 1)] are part of OTUB1-containing complexes, pointing towards a molecular function of this deubiquitinating enzyme in RNA processing and cell adhesion/morphology.

Structural basis and specificity of human otubain 1-mediated deubiquitination.,Edelmann MJ, Iphofer A, Akutsu M, Altun M, di Gleria K, Kramer HB, Fiebiger E, Dhe-Paganon S, Kessler BM Biochem J. 2009 Mar 1;418(2):379-90. PMID:18954305^[15]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Balakirev MY, Tcherniuk SO, Jaquinod M, Chroboczek J. Otubains: a new family of cysteine proteases in the ubiquitin pathway. EMBO Rep. 2003 May;4(5):517-22. PMID:12704427 doi:10.1038/sj.embor.embor824
↑ Soares L, Seroogy C, Skrenta H, Anandasabapathy N, Lovelace P, Chung CD, Engleman E, Fathman CG. Two isoforms of otubain 1 regulate T cell anergy via GRAIL. Nat Immunol. 2004 Jan;5(1):45-54. Epub 2003 Dec 7. PMID:14661020 doi:10.1038/ni1017
↑ Borodovsky A, Ovaa H, Kolli N, Gan-Erdene T, Wilkinson KD, Ploegh HL, Kessler BM. Chemistry-based functional proteomics reveals novel members of the deubiquitinating enzyme family. Chem Biol. 2002 Oct;9(10):1149-59. PMID:12401499
↑ Stanisic V, Malovannaya A, Qin J, Lonard DM, O'Malley BW. OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity. J Biol Chem. 2009 Jun 12;284(24):16135-45. doi: 10.1074/jbc.M109.007484. Epub, 2009 Apr 21. PMID:19383985 doi:10.1074/jbc.M109.007484
↑ Wang T, Yin L, Cooper EM, Lai MY, Dickey S, Pickart CM, Fushman D, Wilkinson KD, Cohen RE, Wolberger C. Evidence for bidentate substrate binding as the basis for the K48 linkage specificity of otubain 1. J Mol Biol. 2009 Mar 6;386(4):1011-23. doi: 10.1016/j.jmb.2008.12.085. Epub 2009 , Jan 13. PMID:19211026 doi:10.1016/j.jmb.2008.12.085
↑ Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC, O'Donnell L, Kumakubo A, Munro M, Sicheri F, Gingras AC, Natsume T, Suda T, Durocher D. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature. 2010 Aug 19;466(7309):941-6. doi: 10.1038/nature09297. PMID:20725033 doi:10.1038/nature09297
↑ Edelmann MJ, Iphofer A, Akutsu M, Altun M, di Gleria K, Kramer HB, Fiebiger E, Dhe-Paganon S, Kessler BM. Structural basis and specificity of human otubain 1-mediated deubiquitination. Biochem J. 2009 Mar 1;418(2):379-90. PMID:18954305 doi:10.1042/BJ20081318
↑ Balakirev MY, Tcherniuk SO, Jaquinod M, Chroboczek J. Otubains: a new family of cysteine proteases in the ubiquitin pathway. EMBO Rep. 2003 May;4(5):517-22. PMID:12704427 doi:10.1038/sj.embor.embor824
↑ Soares L, Seroogy C, Skrenta H, Anandasabapathy N, Lovelace P, Chung CD, Engleman E, Fathman CG. Two isoforms of otubain 1 regulate T cell anergy via GRAIL. Nat Immunol. 2004 Jan;5(1):45-54. Epub 2003 Dec 7. PMID:14661020 doi:10.1038/ni1017
↑ Borodovsky A, Ovaa H, Kolli N, Gan-Erdene T, Wilkinson KD, Ploegh HL, Kessler BM. Chemistry-based functional proteomics reveals novel members of the deubiquitinating enzyme family. Chem Biol. 2002 Oct;9(10):1149-59. PMID:12401499
↑ Stanisic V, Malovannaya A, Qin J, Lonard DM, O'Malley BW. OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity. J Biol Chem. 2009 Jun 12;284(24):16135-45. doi: 10.1074/jbc.M109.007484. Epub, 2009 Apr 21. PMID:19383985 doi:10.1074/jbc.M109.007484
↑ Wang T, Yin L, Cooper EM, Lai MY, Dickey S, Pickart CM, Fushman D, Wilkinson KD, Cohen RE, Wolberger C. Evidence for bidentate substrate binding as the basis for the K48 linkage specificity of otubain 1. J Mol Biol. 2009 Mar 6;386(4):1011-23. doi: 10.1016/j.jmb.2008.12.085. Epub 2009 , Jan 13. PMID:19211026 doi:10.1016/j.jmb.2008.12.085
↑ Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC, O'Donnell L, Kumakubo A, Munro M, Sicheri F, Gingras AC, Natsume T, Suda T, Durocher D. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature. 2010 Aug 19;466(7309):941-6. doi: 10.1038/nature09297. PMID:20725033 doi:10.1038/nature09297
↑ Edelmann MJ, Iphofer A, Akutsu M, Altun M, di Gleria K, Kramer HB, Fiebiger E, Dhe-Paganon S, Kessler BM. Structural basis and specificity of human otubain 1-mediated deubiquitination. Biochem J. 2009 Mar 1;418(2):379-90. PMID:18954305 doi:10.1042/BJ20081318
↑ Edelmann MJ, Iphofer A, Akutsu M, Altun M, di Gleria K, Kramer HB, Fiebiger E, Dhe-Paganon S, Kessler BM. Structural basis and specificity of human otubain 1-mediated deubiquitination. Biochem J. 2009 Mar 1;418(2):379-90. PMID:18954305 doi:10.1042/BJ20081318

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2zfy"

@@ Line 1: / Line 1: @@
-[[Image:2zfy.jpg|left|200px]]<br /><applet load="2zfy" size="350" color="white" frame="true" align="right" spinBox="true"
-caption="2zfy, resolution 1.69&Aring;" />
-'''Crystal structure of human Otubain 1'''<br />
-==About this Structure==
+==Crystal structure of human Otubain 1==
-ZFY is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of 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=2ZFY OCA].
+<StructureSection load='2zfy' size='340' side='right'caption='[[2zfy]], [[Resolution|resolution]] 1.69&Aring;' scene=''>
-[[Category: Homo sapiens]]
+== Structural highlights ==
-[[Category: Single protein]]
+<table><tr><td colspan='2'>[[2zfy]] is a 1 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=2ZFY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2ZFY FirstGlance]. <br>
-[[Category: Akutsu, M.]]
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.69&#8491;</td></tr>
-[[Category: Arrowsmith, C H.]]
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2zfy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2zfy OCA], [https://pdbe.org/2zfy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2zfy RCSB], [https://www.ebi.ac.uk/pdbsum/2zfy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2zfy ProSAT]</span></td></tr>
-[[Category: Bochkarev, A.]]
+</table>
-[[Category: Dhe-Paganon, S.]]
+== Function ==
-[[Category: Edwards, A M.]]
+[https://www.uniprot.org/uniprot/OTUB1_HUMAN OTUB1_HUMAN] Hydrolase that can specifically remove 'Lys-48'-linked conjugated ubiquitin from proteins and plays an important regulatory role at the level of protein turnover by preventing degradation. Regulator of T-cell anergy, a phenomenon that occurs when T-cells are rendered unresponsive to antigen rechallenge and no longer respond to their cognate antigen. Acts via its interaction with RNF128/GRAIL, a crucial inductor of CD4 T-cell anergy. Isoform 1 destabilizes RNF128, leading to prevent anergy. In contrast, isoform 2 stabilizes RNF128 and promotes anergy. Surprisingly, it regulates RNF128-mediated ubiquitination, but does not deubiquitinate polyubiquitinated RNF128. Deubiquitinates estrogen receptor alpha (ESR1). Mediates deubiquitination of 'Lys-48'-linked polyubiquitin chains, but not 'Lys-63'-linked polyubiquitin chains. Not able to cleave di-ubiquitin. Also capable of removing NEDD8 from NEDD8 conjugates, but with a much lower preference compared to 'Lys-48'-linked ubiquitin.<ref>PMID:12704427</ref> <ref>PMID:14661020</ref> <ref>PMID:12401499</ref> <ref>PMID:19383985</ref> <ref>PMID:19211026</ref> <ref>PMID:20725033</ref> <ref>PMID:18954305</ref>   Plays a key non-catalytic role in DNA repair regulation by inhibiting activity of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites. Inhibits RNF168 independently of ubiquitin thioesterase activity by binding and inhibiting UBE2N/UBC13, the E2 partner of RNF168, thereby limiting spreading of 'Lys-63'-linked histone H2A and H2AX marks. Inhibition occurs by binding to free ubiquitin: free ubiquitin acts as an allosteric regulator that increases affinity for UBE2N/UBC13 and disrupts interaction with UBE2V1. The OTUB1-UBE2N/UBC13-free ubiquitin complex adopts a configuration that mimics a cleaved 'Lys48'-linked di-ubiquitin chain.<ref>PMID:12704427</ref> <ref>PMID:14661020</ref> <ref>PMID:12401499</ref> <ref>PMID:19383985</ref> <ref>PMID:19211026</ref> <ref>PMID:20725033</ref> <ref>PMID:18954305</ref>
-[[Category: Li, Y.]]
+== Evolutionary Conservation ==
-[[Category: SGC, Structural Genomics Consortium.]]
+[[Image:Consurf_key_small.gif|200px|right]]
-[[Category: Walker, J R.]]
+Check<jmol>
-[[Category: Weigelt, J.]]
+  <jmolCheckbox>
-[[Category: alternative splicing]]
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zf/2zfy_consurf.spt"</scriptWhenChecked>
-[[Category: hydrolase]]
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
-[[Category: immune response]]
+    <text>to colour the structure by Evolutionary Conservation</text>
-[[Category: otu]]
+  </jmolCheckbox>
-[[Category: otubain]]
+</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=2zfy ConSurf].
-[[Category: phosphoprotein]]
+<div style="clear:both"></div>
-[[Category: protease]]
+<div style="background-color:#fffaf0;">
-[[Category: sgc]]
+== Publication Abstract from PubMed ==
-[[Category: structural genomics]]
+OTUB (otubain) 1 is a human deubiquitinating enzyme that is implicated in mediating lymphocyte antigen responsiveness, but whose molecular function is generally not well defined. A structural analysis of OTUB1 shows differences in accessibility to the active site and in surface properties of the substrate-binding regions when compared with its close homologue, OTUB2, suggesting variations in regulatory mechanisms and substrate specificity. Biochemical analysis reveals that OTUB1 has a preference for cleaving Lys(48)-linked polyubiquitin chains over Lys(63)-linked polyubiquitin chains, and it is capable of cleaving NEDD8 (neural-precursor-cell-expressed developmentally down-regulated 8), but not SUMO (small ubiquitin-related modifier) 1/2/3 and ISG15 (interferon-stimulated gene 15) conjugates. A functional comparison of OTUB1 and OTUB2 indicated a differential reactivity towards ubiquitin-based active-site probes carrying a vinyl methyl ester, a 2-chloroethyl or a 2-bromoethyl group at the C-terminus. Mutational analysis suggested that a narrow P1' site, as observed in OTUB1, correlates with its ability to preferentially cleave Lys(48)-linked ubiquitin chains. Analysis of cellular interaction partners of OTUB1 by co-immunoprecipitation and MS/MS (tandem mass spectrometry) experiments demonstrated that FUS [fusion involved in t(12;6) in malignant liposarcoma; also known as TLS (translocation in liposarcoma) or CHOP (CCAAT/enhancer-binding protein homologous protein)] and RACK1 [receptor for activated kinase 1; also known as GNB2L1 (guanine-nucleotide-binding protein beta polypeptide 2-like 1)] are part of OTUB1-containing complexes, pointing towards a molecular function of this deubiquitinating enzyme in RNA processing and cell adhesion/morphology.
-[[Category: structural genomics consortium]]
-[[Category: thiol protease]]
-[[Category: ubl conjugation pathway]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 19:01:39 2008''
+Structural basis and specificity of human otubain 1-mediated deubiquitination.,Edelmann MJ, Iphofer A, Akutsu M, Altun M, di Gleria K, Kramer HB, Fiebiger E, Dhe-Paganon S, Kessler BM Biochem J. 2009 Mar 1;418(2):379-90. PMID:18954305<ref>PMID:18954305</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 2zfy" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Thioesterase 3D structures|Thioesterase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Akutsu M]]
+[[Category: Arrowsmith CH]]
+[[Category: Bochkarev A]]
+[[Category: Dhe-Paganon S]]
+[[Category: Edwards AM]]
+[[Category: Li Y]]
+[[Category: Walker JR]]
+[[Category: Weigelt J]]

2zfy

From Proteopedia

Current revision

Crystal structure of human Otubain 1

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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