| IED ID | IndEnz0002013065 |
| Enzyme Type ID | protease013065 |
| Protein Name |
Ubiquitin carboxyl-terminal hydrolase 15 EC 3.4.19.12 Deubiquitinating enzyme 15 Ubiquitin thioesterase 15 Ubiquitin-specific-processing protease 15 Unph-2 Unph4 |
| Gene Name | USP15 KIAA0529 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MAEGGAADLDTQRSDIATLLKTSLRKGDTWYLVDSRWFKQWKKYVGFDSWDKYQMGDQNVYPGPIDNSGLLKDGDAQSLKEHLIDELDYILLPTEGWNKLVSWYTLMEGQEPIARKVVEQGMFVKHCKVEVYLTELKLCENGNMNNVVTRRFSKADTIDTIEKEIRKIFSIPDEKETRLWNKYMSNTFEPLNKPDSTIQDAGLYQGQVLVIEQKNEDGTWPRGPSTPKSPGASNFSTLPKISPSSLSNNYNNMNNRNVKNSNYCLPSYTAYKNYDYSEPGRNNEQPGLCGLSNLGNTCFMNSAIQCLSNTPPLTEYFLNDKYQEELNFDNPLGMRGEIAKSYAELIKQMWSGKFSYVTPRAFKTQVGRFAPQFSGYQQQDCQELLAFLLDGLHEDLNRIRKKPYIQLKDADGRPDKVVAEEAWENHLKRNDSIIVDIFHGLFKSTLVCPECAKISVTFDPFCYLTLPLPMKKERTLEVYLVRMDPLTKPMQYKVVVPKIGNILDLCTALSALSGIPADKMIVTDIYNHRFHRIFAMDENLSSIMERDDIYVFEININRTEDTEHVIIPVCLREKFRHSSYTHHTGSSLFGQPFLMAVPRNNTEDKLYNLLLLRMCRYVKISTETEETEGSLHCCKDQNINGNGPNGIHEEGSPSEMETDEPDDESSQDQELPSENENSQSEDSVGGDNDSENGLCTEDTCKGQLTGHKKRLFTFQFNNLGNTDINYIKDDTRHIRFDDRQLRLDERSFLALDWDPDLKKRYFDENAAEDFEKHESVEYKPPKKPFVKLKDCIELFTTKEKLGAEDPWYCPNCKEHQQATKKLDLWSLPPVLVVHLKRFSYSRYMRDKLDTLVDFPINDLDMSEFLINPNAGPCRYNLIAVSNHYGGMGGGHYTAFAKNKDDGKWYYFDDSSVSTASEDQIVSKAAYVLFYQRQDTFSGTGFFPLDRETKGASAATGIPLESDEDSNDNDNDIENENCMHTN |
| Enzyme Length | 981 |
| Uniprot Accession Number | Q9Y4E8 |
| Absorption | |
| Active Site | ACT_SITE 298; /note="Nucleophile"; /evidence="ECO:0000255|PROSITE-ProRule:PRU01035, ECO:0000305|PubMed:19553310, ECO:0000305|PubMed:21947082, ECO:0000305|PubMed:22344298, ECO:0000305|PubMed:24852371, ECO:0000305|PubMed:27368102, ECO:0000305|PubMed:33093067"; ACT_SITE 891; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU10092, ECO:0000255|PROSITE-ProRule:PRU10093" |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Thiol-dependent hydrolysis of ester, thioester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).; EC=3.4.19.12; Evidence={ECO:0000269|PubMed:10444327, ECO:0000269|PubMed:16005295, ECO:0000269|PubMed:21947082, ECO:0000269|PubMed:22344298, ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:33093067}; |
| DNA Binding | |
| EC Number | 3.4.19.12 |
| Enzyme Function | FUNCTION: Hydrolase that removes conjugated ubiquitin from target proteins and regulates various pathways such as the TGF-beta receptor signaling, NF-kappa-B and RNF41/NRDP1-PRKN pathways (PubMed:21947082, PubMed:22344298, PubMed:24852371, PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). 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, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains (PubMed:33093067). May also regulate gene expression and/or DNA repair through the deubiquitination of histone H2B (PubMed:24526689). Acts as an inhibitor of mitophagy by counteracting the action of parkin (PRKN): hydrolyzes cleavage of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains attached by parkin on target proteins such as MFN2, thereby reducing parkin's ability to drive mitophagy (PubMed:24852371). 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 (PubMed:16005295, PubMed:17318178, PubMed:19826004, PubMed:19576224). Involved in endosome organization by mediating deubiquitination of SQSTM1: ubiquitinated SQSTM1 forms a molecular bridge that restrains cognate vesicles in the perinuclear region and its deubiquitination releases target vesicles for fast transport into the cell periphery (PubMed:27368102). Acts as a negative regulator of antifungal immunity by mediating 'Lys-27'-linked deubiquitination of CARD9, thereby inactivating CARD9 (PubMed:33093067). {ECO:0000269|PubMed:16005295, ECO:0000269|PubMed:17318178, ECO:0000269|PubMed:19576224, ECO:0000269|PubMed:19826004, ECO:0000269|PubMed:21947082, ECO:0000269|PubMed:22344298, ECO:0000269|PubMed:24526689, ECO:0000269|PubMed:24852371, ECO:0000269|PubMed:27368102, ECO:0000269|PubMed:33093067}.; FUNCTION: (Microbial infection) Protects APC and human papillomavirus type 16 protein E6 against degradation via the ubiquitin proteasome pathway. {ECO:0000269|PubMed:19553310}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Alternative sequence (4); Beta strand (33); Chain (1); Compositional bias (4); Domain (2); Helix (21); Initiator methionine (1); Modified residue (7); Mutagenesis (2); Region (4); Sequence conflict (3); Turn (7) |
| Keywords | 3D-structure;Acetylation;Alternative splicing;Cytoplasm;Direct protein sequencing;Host-virus interaction;Hydrolase;Mitochondrion;Nucleus;Phosphoprotein;Protease;Reference proteome;Thiol protease;Ubl conjugation;Ubl conjugation pathway |
| Interact With | Q9H257; Q2TAC2; Q0VD86; Q9Y6D9; Q96EA4; Q86TM6; Q6ZNK6; P19474; Q9BTM9; Itself; G5E9A7; P57678; Q08379; Q9NYA3; P02545; Q9Y6D9; Q4G0R1; Q7Z699; Q8IYF3-3 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:21947082, ECO:0000269|PubMed:24526689}. Nucleus {ECO:0000269|PubMed:21947082, ECO:0000269|PubMed:24526689}. Mitochondrion {ECO:0000269|PubMed:24852371}. |
| Modified Residue | MOD_RES 2; /note="N-acetylalanine"; /evidence="ECO:0000269|Ref.8, ECO:0007744|PubMed:19413330, ECO:0007744|PubMed:22223895, ECO:0007744|PubMed:22814378"; MOD_RES 226; /note="Phosphothreonine"; /evidence="ECO:0007744|PubMed:23186163"; MOD_RES 229; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:16964243, ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"; MOD_RES 242; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163"; MOD_RES 602; /note="Phosphothreonine"; /evidence="ECO:0000250|UniProtKB:Q8R5H1"; MOD_RES 961; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231"; MOD_RES 965; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231" |
| Post Translational Modification | PTM: Phosphorylated. Phosphorylation protects against ubiquitination and subsequent degradation by the proteasome. {ECO:0000269|PubMed:16005295}.; PTM: Ubiquitinated, leading to degradation by the proteasome. {ECO:0000269|PubMed:16005295}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (1); X-ray crystallography (13) |
| Cross Reference PDB | 1W6V; 3LMN; 3PPA; 3PV1; 3T9L; 4A3O; 4A3P; 5JJW; 6CPM; 6CRN; 6DJ9; 6GH9; 6GHA; 6ML1; |
| Mapped Pubmed ID | 16027725; 17353931; 17478428; 19373254; 19615732; 19738201; 20379614; 21219870; 23105109; 23524849; 23606334; 23708518; 23727018; 24399297; 24777531; 24811749; 24850914; 24939309; 25416956; 26061460; 26435193; 26496610; 27255711; 27416755; 27460547; 28074857; 28088760; 28126338; 28276505; 28344757; 29263274; 29429988; 29593334; 29895155; 30228188; 30626683; 30713027; 30874560; 31330151; 32101751; 32875609; 33135363; 33267707; 33378683; 33771975; 33946990; 34280614; 34546211; 34583995; |
| Motif | |
| Gene Encoded By | |
| Mass | 112,419 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |