OTU (ovarian tumor) domain family; The OTU family of cysteine proteases use a conserved cysteine and histidine, and in most cases an aspartate, as the catalytic triad. OTU domains typically function as deubiquitinases (DUBs)/ubiquitin thiolesterases (EC 3.4.19.12) that catalyze the thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin, a small regulatory protein that can be conjugated to a large range of target proteins. Protein ubiquitination is a post-translational modification of mostly Lys residues that regulates many cellular processes, including protein degradation, intracellular trafficking, cell signaling, autophagy, transcription, translation, and the DNA damage response. These DUBs may play important regulatory roles at the level of protein turnover by preventing degradation.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    1 MACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREPNVSPSQVTENNFPEKVLLCFSN 80
Cdd:cd22794  42 KACVDYLRRNREKFEAFIEGPFEQYLKNLENPKEWAGQVEISALSLMYKRDFIIYQEPGKPPSNVTENGFPDKILLCFSN 121

                ....*....
gi 8923779   81 GNHYDIVYP 89
Cdd:cd22794 122 GNHYDSVYP 130

OTU (ovarian tumor) domain of OTU domain-containing protein 4 and similar proteins; OTU domain-containing protein 4 (OTUD4), also called HIV-1-induced protein HIN-1, is a deubiquitinase that specifically deubiquitinates 'Lys-63'-polyubiquitinated MYD88 adapter protein upon phosphorylation, triggering down-regulation of NF-kappa-B-dependent transcription of inflammatory mediators. OTUD4 belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    1 MACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREPNVSPSQVTENNFPEKVLLCFSN 80
Cdd:cd22794  42 KACVDYLRRNREKFEAFIEGPFEQYLKNLENPKEWAGQVEISALSLMYKRDFIIYQEPGKPPSNVTENGFPDKILLCFSN 121

                ....*....
gi 8923779   81 GNHYDIVYP 89
Cdd:cd22794 122 GNHYDSVYP 130

OTU (ovarian tumor) domain of OTU domain-containing protein 4 and similar proteins; OTU domain-containing protein 4 (OTUD4), also called HIV-1-induced protein HIN-1, is a deubiquitinase that specifically deubiquitinates 'Lys-63'-polyubiquitinated MYD88 adapter protein upon phosphorylation, triggering down-regulation of NF-kappa-B-dependent transcription of inflammatory mediators. OTUD4 belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    1 MACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREPNVSPSQVTENNFPEKVLLCFSN 80
Cdd:cd22794  42 KACVDYLRRNREKFEAFIEGPFEQYLKNLENPKEWAGQVEISALSLMYKRDFIIYQEPGKPPSNVTENGFPDKILLCFSN 121

                ....*....
gi 8923779   81 GNHYDIVYP 89
Cdd:cd22794 122 GNHYDSVYP 130

OTU (ovarian tumor) domain of bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 and similar proteins; Bifunctional UDP-N-acetylglucosamine transferase and deubiquitinase ALG13 is alco called asparagine-linked glycosylation 13 homolog, glycosyltransferase 28 domain-containing protein 1 (GLT28D1), or UDP-N-acetylglucosamine transferase subunit ALG13 homolog. It displays both glycosyltransferase (EC 2.4.1.141) and deubiquitinase (DUB)/ubiquitin thioesterase (EC 3.4.19.12) activities. With ALG14, it forms a UDP-N-acetylglucosamine transferase that catalyzes the second step of eukaryotic N-linked glycosylation in the endoplasmic reticulum. ALG13 variants cause a form of early infantile epileptic encephalopathy known as EIEE36 refractory seizures, neurodevelopmental impairment, and poor prognosis; given the essential role of ALG13 in glycosylation, it is also considered a congenital disorder of glycosylation (CDG). This subfamily also contains OTU domain-containing protein 4 (OTUD4), also called HIV-1-induced protein HIN-1, a DUB that specifically deubiquitinates 'Lys-63'-polyubiquitinated MYD88 adapter protein upon phosphorylation, triggering down-regulation of NF-kappa-B-dependent transcription of inflammatory mediators. This subfamily belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    2 ACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREPNVSPSQVTENNFPEKVLLCFSNG 81
Cdd:cd22753  43 ACVEYLEKNREEFEKFSEISFDDYLERLSDPKEWGGLLELEALSLLYKVDFIVYSIPDQPPSNITNNGYPKKIMLCYSGG 122

                ....*...
gi 8923779   82 NHYDIVYP 89
Cdd:cd22753 123 NHYDSVYS 130

OTU (ovarian tumor) domain of Arabidopsis thaliana deubiquitinating enzyme OTU7 and similar proteins; Arabidopsis thaliana deubiquitinating enzyme OTU7, also called OTU domain-containing protein 7, is a deubiquitinase (DUB)/ubiquitin thioesterase (EC 3.4.19.12) that shows a preference for 'Lys-63' over 'Lys-48' over 'Met-1'-linked ubiquitin (UB) tetramers as substrates. DUBs catalyze the thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin, a small regulatory protein that can be conjugated to a large range of target proteins. Protein ubiquitination is a post-translational modification of mostly Lys residues that regulates many cellular processes, including protein degradation, intracellular trafficking, cell signaling, autophagy, transcription, translation, and the DNA damage response. These DUBs may play important regulatory roles at the level of protein turnover by preventing degradation. OTU7 belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    2 ACIHYLRENREKFEAFIEG--SFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREpNVSPSQVTenNFPEK----VL 75
Cdd:cd22771  35 KVVDYMEAHEEDFEPFFEDdeTFEDYVSRMREDGTWGGNLELQAASLVYRVNIVVHQL-GQPRWEIE--NFPDKgartIH 111

                        90
                ....*....|..
gi 8923779   76 LCFSNGNHYDIV 87
Cdd:cd22771 112 LSYHDGEHYNSV 123

OTU (ovarian tumor) domain of OTU domain-containing proteins 6A, 6B, and similar proteins; This subfamily is composed of mammalian OTU domain-containing protein 6A (OTUD6A, also called DUBA-2, vertebrate OTU domain-containing protein 6B (OTUD6B, also called DUBA-5), fungal OTU domain-containing protein 2 (OTU2), and similar proteins. OTUD6A, OTUD6B, and Schizosaccharomyces pombe OTU2 are deubiquitinating enzymes/ubiquitinyl hydrolases (EC 3.4.19.12). OTUD6A hydrolyzes 'Lys-27'-, 'Lys-29'-, and 'Lys-33'-linked polyubiquitin chains, and may also be able to hydrolyze 'Lys-11'-linked ubiquitin chains. It deubiquitylates and stabilizes dynamin-related protein 1 (Drp1), a cytosolic protein responsible for mitochondrial fission and is essential in the initiation and development of several human diseases including cancer, thereby facilitating tumorigenesis. OTUD6B is a functional deubiquitinase in in vitro enzyme assays. It may play a role in the ubiquitin-dependent regulation of protein synthesis downstream of mTORC1, and may modify the ubiquitination of the protein synthesis initiation complex to repress translation. Biallelic variants in OTUD6B cause an intellectual disability syndrome that is associated with seizures and dysmorphic features. This subfamily belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    6 YLRENREKFEAFI---------EGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYREPnvSPSQVTENNFPEK--V 74
Cdd:cd22748  48 YMRAHRDDFLPFLtnddgdlmtEEEFEEYCDKIENTAEWGGQLELRALSKALKRPIHVYQAG--SPPLVIGEEFDSGepL 125

                        90
                ....*....|....*
gi 8923779   75 LLCF-----SNGNHY 84
Cdd:cd22748 126 RLSYhrhayGLGEHY 140

OTU (ovarian tumor) domain of OTU domain-containing protein 5 and similar proteins; OTU domain-containing protein 5 (OTUD5), also called deubiquitinating enzyme A (DUBA), is a phosphorylation-dependent deubiquitinase (DUB)/ubiquitin thioesterase (EC 3.4.19.12) that can hydrolyze 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains, and may function as negative regulator of the innate immune system. It limits type I interferon production in macrophages and suppresses interleukin-17A production in T cells. OTUD5 also functions in an apoptotic signaling cascade by mediating the sequential activation of PDCD5 (programmed cell death 5) and p53 in response to genotoxic stress. In Drosophila, OTUD5/DUBA is essential for spermatogenesis. This subfamily also includes Arabidopsis thaliana OTU domain-containing protein 6, also called deubiquitinating enzyme OTU6 or otubain-like deubiquitinase 1 (OTLD1), which binds chromatin and has enzymatic histone deubiquitinase activity specific for the H2B histone. This subfamily belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad. It also includes plant OTU6.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    2 ACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIY---REP-NVSPSQVTENNFPekVLLC 77
Cdd:cd22752  35 HCMDYMEKNRDYFSQFVTEDFEEYINRKRQDGVWGNHIEIQAMSELYNRPIEVYaysTEPiNTFHEASSSDNEP--IRLS 112

                        90
                ....*....|..
gi 8923779   78 FSNGNHYDIVYP 89
Cdd:cd22752 113 YHGNSHYNSIVD 124

OTU-like cysteine protease; This family is comprised of a group of predicted cysteine proteases, homologous to the Ovarian Tumour (OTU) gene in Drosophila. Members include proteins from eukaryotes, viruses and pathogenic bacterium. The conserved cysteine and histidine, and possibly the aspartate, represent the catalytic residues in this putative group of proteases.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 8923779      2 ACIHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYR 56
Cdd:pfam02338  33 TLAEYMREHKEEFEPFLEDDETGDIIEIEQTGAWGGEIEIFALAHILRRPIIVYK 87

OTU (ovarian tumor) domain of deubiquitinating enzymes OTU3 and OTU4 from plants, and similar proteins; Deubiquitinating enzyme OTU3 (also called OTU domain-containing protein 3) and deubiquitinating enzyme OTU4 (also called OTU domain-containing protein 4) are deubiquitinases (DUBs) or ubiquitin thiolesterases (EC 3.4.19.12) that catalyze the thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin, a small regulatory protein that can be conjugated to a large range of target proteins. Protein ubiquitination is a post-translational modification of mostly Lys residues that regulates many cellular processes, including protein degradation, intracellular trafficking, cell signaling, autophagy, transcription, translation, and the DNA damage response. OTU3 and OTU4 may play important regulatory roles at the level of protein turnover by preventing degradation. They belong to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    1 MACIHYLRENREKFEA---FIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIY----REPNVSPSQVTENNFP-- 71
Cdd:cd22746  45 KAVVEEIRKRRDELFEgslVIEGDFDAYCQRMSHPDTWGGEPELLMLADVLQRPIAVYlptpGKGGLRKIQEYGEEYLgg 124

                        90
                ....*....|....
gi 8923779   72 EKVLLCFSNGNHYD 85
Cdd:cd22746 125 EPIRLLYNGGNHYD 138

OTU (ovarian tumor) domain of deubiquitinating enzyme OTU3 from plants and similar proteins; Deubiquitinating enzyme OTU3, also called OTU domain-containing protein 3, is a deubiquitinase (DUB) or ubiquitin thiolesterase (EC 3.4.19.12) that catalyzes the thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin, a small regulatory protein that can be conjugated to a large range of target proteins. Protein ubiquitination is a post-translational modification of mostly Lys residues that regulates many cellular processes, including protein degradation, intracellular trafficking, cell signaling, autophagy, transcription, translation, and the DNA damage response. OTU3 may play an important regulatory role at the level of protein turnover by preventing degradation. OTU3 belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    8 RENREKFEAFI----EGSFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIYRE----------PNVSPSQVTENNFPEK 73
Cdd:cd22759  56 ERRRDYEEALIaitvEGSLDRYCRRIQRPDFWGGESELLVLSKMLKQPIIVYIPeseaknggwgSGFIPIQKYGEEFAKG 135

                        90       100
                ....*....|....*....|..
gi 8923779   74 ---------VLLCFSNGNHYDI 86
Cdd:cd22759 136 tkgrkgrkpVRLLYSGSNHYDL 157

OTU (ovarian tumor) domain of Caenorhabditis elegans deubiquitylating enzyme with USP/UBP and OTU domains, and similar proteins; This subfamily is composed of mostly uncharacterized proteins containing an OTU domain, similar to Caenorhabditis elegans deubiquitylating enzyme with USP/UBP and OTU domains. OTU domain-containing proteins function as deubiquitinases (DUBs)/ubiquitin thiolesterases (EC 3.4.19.12) that catalyze the thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin, a small regulatory protein that can be conjugated to a large range of target proteins. Protein ubiquitination is a post-translational modification of mostly Lys residues that regulates many cellular processes, including protein degradation, intracellular trafficking, cell signaling, autophagy, transcription, translation, and the DNA damage response. These DUBs may play important regulatory roles at the level of protein turnover by preventing degradation. They belong to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    1 MACIHYLRENREKFEAFI---EGSFEEYLKRLENPQ--EWVGQVEISALSLMYRKDFIIY---------REPNVSPSQVT 66
Cdd:cd22755  33 KAIVDFLEKNPDEFRNLLrsdYESVEEYLEKSRMRYdgTWATDVEIFAAATLLGVDIYVYskggykwllYSPRFKLGKRN 112

                        90       100
                ....*....|....*....|.
gi 8923779   67 ENNFPekVLLCFSNGNHYDIV 87
Cdd:cd22755 113 GSREA--IYLKNTNGNHFEPV 131

OTU (ovarian tumor) domain of deubiquitinating enzyme OTU5 from plants and similar proteins; Deubiquitinating enzyme OTU5, also called OTU domain-containing protein 6, is a deubiquitinase (DUB) or ubiquitin thiolesterase (EC 3.4.19.12) that catalyzes the thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin, a small regulatory protein that can be conjugated to a large range of target proteins. Protein ubiquitination is a post-translational modification of mostly Lys residues that regulates many cellular processes, including protein degradation, intracellular trafficking, cell signaling, autophagy, transcription, translation, and the DNA damage response. OTU5 is an inactive cysteine protease. It regulates gene expression by contributing to chromatin organization and DNA methylation patterns (e.g. H3K4me3 and H3K27me3). It is required for phosphate (Pi) homeostasis. OTU5 belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50
                ....*....|....*....|....*....|....*....|....*....|....*....
gi 8923779    6 YLRENREKFEAFIEG---------SFEEYLKRLENPQEWVGQVEISALSLMYRKDFIIY 55
Cdd:cd22797  52 YMRAHPDDFLPFLEDedeggdgdeAFEAYCREVESTAAWGGQLELGALAHALRRHIKVY 110

OTU (ovarian tumor) domain of OTU domain-containing protein 1 and similar proteins; OTU domain-containing protein 1 (OTUD1), also called DUBA-7 in humans, is a deubiquitinating enzyme/ubiquitinyl hydrolase (EC 3.4.19.12) that specifically hydrolyzes 'Lys-63'-linked polyubiquitin to monoubiquitin; this specificity is facilitated by the C-terminal Ub-interacting motif (UIM) of OTUD1. It interacts and promotes the deubiquitination of myeloid cell leukemia 1 (MCL1), a pro-survival Bcl-2 family protein that plays important roles in cell survival, proliferation, differentiation and tumorigenesis. OTUD1 also deubiquitinates IFN regulatory factor 3 (IRF3) and attenuates its function; IRF3 is critical for the transcription of type I IFNs in defensing virus and promoting inflammatory responses. Loss-of-function mutations of OTUD1 associated with multiple autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ulcerative colitis (UC) and Hashimoto's thyroiditis (HT). OTUD1 belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    4 IHYLRENREKFEAFIEGSFEEYLKRLENPQEWVGQVEISALSLMYRKDfiIYREPNVSPSQVT----------ENNFPEK 73
Cdd:cd22747  56 VHYIADHLDEFNPIIEGDVGEFLIKAAQDGAWAGYPELLAMGQMLNVN--IRLTTGGSLESPTvstmvhylgpEDSGKPS 133

                        90
                ....*....|....*.
gi 8923779   74 VLLCF-SNGnHYDIVY 88
Cdd:cd22747 134 IWLSWlSNG-HYDAVF 148

Otubain subfamily of ubiquitin thioesterases; The otubain subfamily is composed of otubain-1 (also called ubiquitin thioesterase OTUB1 or OTU domain-containing ubiquitin aldehyde-binding protein 1), otubain-2 (also called ubiquitin thioesterase OTUB2 or OTU domain-containing ubiquitin aldehyde-binding protein 2), and similar proteins. They function as deubiquitylases (DUBs)/ubiquitin thioesterases (EC 3.4.19.12). OTUB1 can specifically remove 'Lys-48'-linked conjugated ubiquitin from protein substrates, while OTUB2 mediates the deubiquitination of 'Lys-11'-,'Lys-48'- and 'Lys-63'-linked polyubiquitin chains, with a preference for 'Lys-63'-linked polyubiquitin chains. The otubain subfamily belongs to the OTU family of cysteine proteases that use a conserved cysteine, histidine, and an aspartate, as the catalytic triad. Members of this subfamily are classified as family C65 cysteine proteases by MEROPS.

                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779    6 YLRENREKFEAFIEG--SFEEYLKR-LENPQEWVGQVEISALSLMYRKDF-IIYREpNVSPSQVTENNFPE-------KV 74
Cdd:cd22749 141 YLKTNADDYEPFLFEgmSVEEFCEReVEPMGKEADHLQITALANALGVPVrVEYLD-RSAGGEVNFHEFPPedsdslpVI 219

                        90
                ....*....|....
gi 8923779   75 LLCFSNGnHYDIVY 88
Cdd:cd22749 220 TLLYRPG-HYDILY 232

Peptidase C65 Otubain; This family of proteins conserved from plants to humans is a highly specific ubiquitin iso-peptidase that removes ubiquitin from proteins. The modification of cellular proteins by ubiquitin (Ub) is an important event that underlies protein stability and function in eukaryote being a dynamic and reversible process. Otubain carries several key conserved domains: (i) the OTU (ovarian tumour domain) in which there is an active cysteine protease triad (ii) a nuclear localization signal, (iii) a Ub interaction motif (UIM)-like motif phi-xx-A-xxxs-xx-Ac (where phi indicates an aromatic amino acid, x indicates any amino acid and Ac indicates an acidic amino acid), (iv) a Ub-associated (UBA)-like domain and (v) the LxxLL motif.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 8923779      5 HYLRENREKFEAFIEG--SFEEYLKR-LENPQEWVGQVEISALS--LMYRKDfIIYREPNVSPSQVTENNFPEK------ 73
Cdd:pfam10275 144 AYLKTHADEYEPFIDGggTVEEFCQQeVEPMNKEADHLQIIALAeaLGVPVR-VEYLDRSAEGNTVNHHDFPGEddteeq 222

                          90
                  ....*....|....*....
gi 8923779     74 ---VLLCFSNGnHYDIVYP 89
Cdd:pfam10275 223 apfITLLYRPG-HYDILYK 240