| Structural highlights
4i6l is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | OTUB1, OTB1, OTU1, HSPC263 (HUMAN), UBC (HUMAN) |
| Activity: | Ubiquitinyl hydrolase 1, with EC number 3.4.19.12 |
| 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] [UBC_HUMAN] Ubiquitin exists either covalently attached to another protein, or free (unanchored). When covalently bound, it is conjugated to target proteins via an isopeptide bond either as a monomer (monoubiquitin), a polymer linked via different Lys residues of the ubiquitin (polyubiquitin chains) or a linear polymer linked via the initiator Met of the ubiquitin (linear polyubiquitin chains). Polyubiquitin chains, when attached to a target protein, have different functions depending on the Lys residue of the ubiquitin that is linked: Lys-6-linked may be involved in DNA repair; Lys-11-linked is involved in ERAD (endoplasmic reticulum-associated degradation) and in cell-cycle regulation; Lys-29-linked is involved in lysosomal degradation; Lys-33-linked is involved in kinase modification; Lys-48-linked is involved in protein degradation via the proteasome; Lys-63-linked is involved in endocytosis, DNA-damage responses as well as in signaling processes leading to activation of the transcription factor NF-kappa-B. Linear polymer chains formed via attachment by the initiator Met lead to cell signaling. Ubiquitin is usually conjugated to Lys residues of target proteins, however, in rare cases, conjugation to Cys or Ser residues has been observed. When polyubiquitin is free (unanchored-polyubiquitin), it also has distinct roles, such as in activation of protein kinases, and in signaling.[15] [16]
Publication Abstract from PubMed
The ubiquitin system regulates virtually all aspects of cellular function. We report a method to target the myriad enzymes that govern ubiquitination of protein substrates. We used massively diverse combinatorial libraries of ubiquitin variants to develop inhibitors of four deubiquitinases (DUBs) and analyzed the DUB-inhibitor complexes with crystallography. We extended the selection strategy to the ubiquitin conjugating (E2) and ubiquitin ligase (E3) enzymes and found that ubiquitin variants can also enhance enzyme activity. Last, we showed that ubiquitin variants can bind selectively to ubiquitin-binding domains. Ubiquitin variants exhibit selective function in cells and thus enable orthogonal modulation of specific enzymatic steps in the ubiquitin system.
A strategy for modulation of enzymes in the ubiquitin system.,Ernst A, Avvakumov G, Tong J, Fan Y, Zhao Y, Alberts P, Persaud A, Walker JR, Neculai AM, Neculai D, Vorobyov A, Garg P, Beatty L, Chan PK, Juang YC, Landry MC, Yeh C, Zeqiraj E, Karamboulas K, Allali-Hassani A, Vedadi M, Tyers M, Moffat J, Sicheri F, Pelletier L, Durocher D, Raught B, Rotin D, Yang J, Moran MF, Dhe-Paganon S, Sidhu SS Science. 2013 Feb 1;339(6119):590-5. doi: 10.1126/science.1230161. Epub 2013 Jan , 3. PMID:23287719[17]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Huang F, Kirkpatrick D, Jiang X, Gygi S, Sorkin A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol Cell. 2006 Mar 17;21(6):737-48. PMID:16543144 doi:S1097-2765(06)00120-1
- ↑ Komander D. The emerging complexity of protein ubiquitination. Biochem Soc Trans. 2009 Oct;37(Pt 5):937-53. doi: 10.1042/BST0370937. PMID:19754430 doi:10.1042/BST0370937
- ↑ Ernst A, Avvakumov G, Tong J, Fan Y, Zhao Y, Alberts P, Persaud A, Walker JR, Neculai AM, Neculai D, Vorobyov A, Garg P, Beatty L, Chan PK, Juang YC, Landry MC, Yeh C, Zeqiraj E, Karamboulas K, Allali-Hassani A, Vedadi M, Tyers M, Moffat J, Sicheri F, Pelletier L, Durocher D, Raught B, Rotin D, Yang J, Moran MF, Dhe-Paganon S, Sidhu SS. A strategy for modulation of enzymes in the ubiquitin system. Science. 2013 Feb 1;339(6119):590-5. doi: 10.1126/science.1230161. Epub 2013 Jan , 3. PMID:23287719 doi:10.1126/science.1230161
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