| IED ID | IndEnz0002012319 |
| Enzyme Type ID | protease012319 |
| Protein Name |
Ubiquitin carboxyl-terminal hydrolase 7 EC 3.4.19.12 Deubiquitinating enzyme 7 Herpesvirus-associated ubiquitin-specific protease Ubiquitin thioesterase 7 Ubiquitin-specific-processing protease 7 |
| Gene Name | USP7 HAUSP |
| 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 | MNHQQQQQQQKAGEQQLSEPEDMEMEAGDTDDPPRITQNPVINGNVALSDGHNTAEEDMEDDTSWRSEATFQFTVERFSRLSESVLSPPCFVRNLPWKIMVMPRFYPDRPHQKSVGFFLQCNAESDSTSWSCHAQAVLKIINYRDDEKSFSRRISHLFFHKENDWGFSNFMAWSEVTDPEKGFIDDDKVTFEVFVQADAPHGVAWDSKKHTGYVGLKNQGATCYMNSLLQTLFFTNQLRKAVYMMPTEGDDSSKSVPLALQRVFYELQHSDKPVGTKKLTKSFGWETLDSFMQHDVQELCRVLLDNVENKMKGTCVEGTIPKLFRGKMVSYIQCKEVDYRSDRREDYYDIQLSIKGKKNIFESFVDYVAVEQLDGDNKYDAGEHGLQEAEKGVKFLTLPPVLHLQLMRFMYDPQTDQNIKINDRFEFPEQLPLDEFLQKTDPKDPANYILHAVLVHSGDNHGGHYVVYLNPKGDGKWCKFDDDVVSRCTKEEAIEHNYGGHDDDLSVRHCTNAYMLVYIRESKLSEVLQAVTDHDIPQQLVERLQEEKRIEAQKRKERQEAHLYMQVQIVAEDQFCGHQGNDMYDEEKVKYTVFKVLKNSSLAEFVQSLSQTMGFPQDQIRLWPMQARSNGTKRPAMLDNEADGNKTMIELSDNENPWTIFLETVDPELAASGATLPKFDKDHDVMLFLKMYDPKTRSLNYCGHIYTPISCKIRDLLPVMCDRAGFIQDTSLILYEEVKPNLTERIQDYDVSLDKALDELMDGDIIVFQKDDPENDNSELPTAKEYFRDLYHRVDVIFCDKTIPNDPGFVVTLSNRMNYFQVAKTVAQRLNTDPMLLQFFKSQGYRDGPGNPLRHNYEGTLRDLLQFFKPRQPKKLYYQQLKMKITDFENRRSFKCIWLNSQFREEEITLYPDKHGCVRDLLEECKKAVELGEKASGKLRLLEIVSYKIIGVHQEDELLECLSPATSRTFRIEEIPLDQVDIDKENEMLVTVAHFHKEVFGTFGIPFLLRIHQGEHFREVMKRIQSLLDIQEKEFEKFKFAIVMMGRHQYINEDEYEVNLKDFEPQPGNMSHPRPWLGLDHFNKAPKRSRYTYLEKAIKIHN |
| Enzyme Length | 1102 |
| Uniprot Accession Number | Q93009 |
| Absorption | |
| Active Site | ACT_SITE 223; /note="Nucleophile"; /evidence="ECO:0000269|PubMed:12507430, ECO:0000269|PubMed:25944111, ECO:0000305|PubMed:11923872, ECO:0000305|PubMed:15053880, ECO:0000305|PubMed:16964248, ECO:0000305|PubMed:18716620, ECO:0000305|PubMed:21745816, ECO:0000305|PubMed:22411829"; ACT_SITE 464; /note="Proton acceptor"; /evidence="ECO:0000305|PubMed:12507430" |
| Activity Regulation | ACTIVITY REGULATION: Inhibited by N-ethyl-maleimide (NEM) and divalent cations. Tolerates high concentrations of NaCl but is inhibited at concentrations of 195 mM and higher. {ECO:0000269|PubMed:14506283}. |
| 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:11923872, ECO:0000269|PubMed:12507430, ECO:0000269|PubMed:14506283, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:16964248, ECO:0000269|PubMed:18716620, ECO:0000269|PubMed:21745816, ECO:0000269|PubMed:25865756, ECO:0000269|PubMed:26678539, ECO:0000269|PubMed:28655758}; |
| DNA Binding | |
| EC Number | 3.4.19.12 |
| Enzyme Function | FUNCTION: Hydrolase that deubiquitinates target proteins such as FOXO4, KAT5, p53/TP53, MDM2, ERCC6, DNMT1, UHRF1, PTEN, KMT2E/MLL5 and DAXX (PubMed:11923872, PubMed:15053880, PubMed:16964248, PubMed:18716620, PubMed:25283148, PubMed:25865756, PubMed:26678539, PubMed:28655758). Together with DAXX, prevents MDM2 self-ubiquitination and enhances the E3 ligase activity of MDM2 towards p53/TP53, thereby promoting p53/TP53 ubiquitination and proteasomal degradation (PubMed:15053880, PubMed:16845383, PubMed:18566590, PubMed:20153724). Deubiquitinates p53/TP53, preventing degradation of p53/TP53, and enhances p53/TP53-dependent transcription regulation, cell growth repression and apoptosis (PubMed:25283148). Deubiquitinates p53/TP53 and MDM2 and strongly stabilizes p53/TP53 even in the presence of excess MDM2, and also induces p53/TP53-dependent cell growth repression and apoptosis (PubMed:11923872). Deubiquitination of FOXO4 in presence of hydrogen peroxide is not dependent on p53/TP53 and inhibits FOXO4-induced transcriptional activity (PubMed:16964248). In association with DAXX, is involved in the deubiquitination and translocation of PTEN from the nucleus to the cytoplasm, both processes that are counteracted by PML (PubMed:18716620). Deubiquitinates KMT2E/MLL5 preventing KMT2E/MLL5 proteasomal-mediated degradation (PubMed:26678539). Involved in cell proliferation during early embryonic development. Involved in transcription-coupled nucleotide excision repair (TC-NER) in response to UV damage: recruited to DNA damage sites following interaction with KIAA1530/UVSSA and promotes deubiquitination of ERCC6, preventing UV-induced degradation of ERCC6 (PubMed:22466611, PubMed:22466612). Involved in maintenance of DNA methylation via its interaction with UHRF1 and DNMT1: acts by mediating deubiquitination of UHRF1 and DNMT1, preventing their degradation and promoting DNA methylation by DNMT1 (PubMed:21745816, PubMed:22411829). Deubiquitinates alkylation repair enzyme ALKBH3. OTUD4 recruits USP7 and USP9X to stabilize ALKBH3, thereby promoting the repair of alkylated DNA lesions (PubMed:25944111). Acts as a chromatin regulator via its association with the Polycomb group (PcG) multiprotein PRC1-like complex; may act by deubiquitinating components of the PRC1-like complex (PubMed:20601937). Able to mediate deubiquitination of histone H2B; it is however unsure whether this activity takes place in vivo (PubMed:20601937). Exhibits a preference towards 'Lys-48'-linked ubiquitin chains (PubMed:22689415). Increases regulatory T-cells (Treg) suppressive capacity by deubiquitinating and stabilizing the transcription factor FOXP3 which is crucial for Treg cell function (PubMed:23973222). Plays a role in the maintenance of the circadian clock periodicity via deubiquitination and stabilization of the CRY1 and CRY2 proteins (PubMed:27123980). Deubiquitinates REST, thereby stabilizing REST and promoting the maintenance of neural progenitor cells (PubMed:21258371). Deubiquitinates SIRT7, inhibiting SIRT7 histone deacetylase activity and regulating gluconeogenesis (PubMed:28655758). {ECO:0000269|PubMed:11923872, ECO:0000269|PubMed:15053880, ECO:0000269|PubMed:16845383, ECO:0000269|PubMed:16964248, ECO:0000269|PubMed:18566590, ECO:0000269|PubMed:18716620, ECO:0000269|PubMed:20153724, ECO:0000269|PubMed:20601937, ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:21745816, ECO:0000269|PubMed:22411829, ECO:0000269|PubMed:22466611, ECO:0000269|PubMed:22466612, ECO:0000269|PubMed:22689415, ECO:0000269|PubMed:23973222, ECO:0000269|PubMed:25283148, ECO:0000269|PubMed:25865756, ECO:0000269|PubMed:25944111, ECO:0000269|PubMed:26678539, ECO:0000269|PubMed:27123980, ECO:0000269|PubMed:28655758}.; FUNCTION: (Microbial infection) Contributes to the overall stabilization and trans-activation capability of the herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110 during HSV-1 infection. {ECO:0000269|PubMed:14506283, ECO:0000269|PubMed:16160161, ECO:0000269|PubMed:18590780}. |
| Temperature Dependency | |
| PH Dependency | BIOPHYSICOCHEMICAL PROPERTIES: pH dependence: Active from pH 7.0 to 9.5. {ECO:0000269|PubMed:14506283}; |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Alternative sequence (1); Beta strand (66); Chain (1); Compositional bias (1); Cross-link (3); Domain (2); Helix (45); Modified residue (6); Mutagenesis (6); Region (5); Sequence conflict (5); Turn (14) |
| Keywords | 3D-structure;Acetylation;Alternative splicing;Biological rhythms;Chromosome;Cytoplasm;DNA damage;DNA repair;Developmental protein;Direct protein sequencing;Host-virus interaction;Hydrolase;Isopeptide bond;Nucleus;Phosphoprotein;Protease;Reference proteome;Thiol protease;Ubl conjugation;Ubl conjugation pathway |
| Interact With | Q49AR9; Q6W2J9; P35226; Q9HC52; Q9UER7; P21145; Q00987; O15151; Q5U5Q3; Q99836; P35227; P60484-1; P06400; Q06587; Q99496; P84022; P48431; Q99426; P04637; Q86VY4; P36508; P03211; Q77UV9; O35618; F5H9D8 |
| Induction | INDUCTION: Up-regulated in regulatory T-cells (Treg). Down-regulated during neural progenitor cell differentiation (PubMed:21258371). {ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:23973222}. |
| Subcellular Location | SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:21258371, ECO:0000269|PubMed:23973222, ECO:0000269|PubMed:25283148, ECO:0000269|PubMed:26678539}. Cytoplasm {ECO:0000269|PubMed:25283148}. Nucleus, PML body {ECO:0000269|PubMed:9034339}. Chromosome {ECO:0000269|PubMed:20601937}. Note=Present in a minority of ND10 nuclear bodies. Association with ICP0/VMW110 at early times of infection leads to an increased proportion of USP7-containing ND10. Colocalizes with ATXN1 in the nucleus. Colocalized with DAXX in speckled structures. Colocalized with PML and PTEN in promyelocytic leukemia protein (PML) nuclear bodies. |
| Modified Residue | MOD_RES 18; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:17651432, ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163, ECO:0007744|PubMed:24275569"; MOD_RES 49; /note="Phosphoserine"; /evidence="ECO:0000250|UniProtKB:Q6A4J8"; MOD_RES 869; /note="N6-acetyllysine; alternate"; /evidence="ECO:0007744|PubMed:19608861"; MOD_RES 963; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:17651432, ECO:0007744|PubMed:18669648"; MOD_RES 1084; /note="N6-acetyllysine"; /evidence="ECO:0007744|PubMed:19608861"; MOD_RES 1096; /note="N6-acetyllysine"; /evidence="ECO:0007744|PubMed:19608861" |
| Post Translational Modification | PTM: Isoform 1: Phosphorylated. Isoform 1 is phosphorylated at positions Ser-18 and Ser-963. Isoform 2: Not phosphorylated. {ECO:0000269|PubMed:17651432}.; PTM: Isoform 1: Polyneddylated. Isoform 2: Not Polyneddylated.; PTM: Isoform 1 and isoform 2: Not sumoylated.; PTM: Isoform 1 and isoform 2: Polyubiquitinated by herpesvirus 1 trans-acting transcriptional protein ICP0/VMW110; leading to its subsequent proteasomal degradation. Isoform 1: Ubiquitinated at Lys-869. {ECO:0000269|PubMed:16160161, ECO:0000269|PubMed:17651432}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (1); X-ray crystallography (57) |
| Cross Reference PDB | 1NB8; 1NBF; 1YY6; 1YZE; 2F1W; 2F1X; 2F1Y; 2F1Z; 2FOJ; 2FOO; 2FOP; 2KVR; 2XXN; 2YLM; 3MQR; 3MQS; 4JJQ; 4KG9; 4M5W; 4M5X; 4PYZ; 4WPH; 4WPI; 4YOC; 4YSI; 4Z96; 4Z97; 5C56; 5C6D; 5FWI; 5GG4; 5J7T; 5JTJ; 5JTV; 5KYB; 5KYC; 5KYD; 5KYE; 5KYF; 5N9R; 5N9T; 5NGE; 5NGF; 5UQV; 5UQX; 5VS6; 5VSB; 5VSK; 5WHC; 6F5H; 6M1K; 6P5L; 6VN2; 6VN3; 6VN4; 6VN5; 6VN6; 7CM2; |
| Mapped Pubmed ID | 10944529; 12208738; 12660172; 12783858; 14517266; 14676191; 14743216; 15058298; 15140983; 15494000; 15590680; 15916963; 15942648; 16111684; 16246722; 16713569; 16751180; 16916636; 17000769; 17268548; 17353931; 17442268; 17466625; 17466626; 17643379; 17927229; 17936559; 17948053; 17981804; 18079701; 18410486; 18418047; 18614043; 18729074; 18833293; 18952891; 19124652; 19279666; 19470478; 19615732; 19834552; 19940136; 20195357; 20227374; 20379614; 20541997; 20562859; 20697359; 20713061; 20855462; 20885946; 20930542; 21070792; 21161328; 21268065; 21282463; 21305000; 21468692; 21468693; 21480003; 21490432; 21845734; 21911578; 21981925; 21988832; 22056774; 22072716; 22081108; 22361354; 22466610; 22496234; 22514345; 22634009; 22653443; 22750444; 22810585; 22901115; 22902626; 22993145; 23089923; 23183427; 23267096; 23348568; 23483195; 23524849; 23602568; 23603909; 23752268; 23760561; 23775119; 23902751; 23906714; 23973375; 24127601; 24190967; 24402227; 24598911; 24811749; 24823443; 24832601; 25003721; 25082234; 25118285; 25154395; 25172512; 25260751; 25358258; 25435140; 25435364; 25483066; 25519684; 25605328; 25609649; 25665578; 25694600; 25695151; 25695607; 25836587; 25894431; 25925205; 25960197; 25961918; 26046769; 26129839; 26175158; 26210801; 26224631; 26235645; 26238070; 26299963; 26365382; 26460617; 26496610; 26673319; 26768359; 26786098; 26950370; 26971997; 27129218; 27183383; 27183903; 27302477; 27452404; 27590858; 27618649; 27632941; 27800609; 28137592; 28280111; 28288134; 28325877; 28406480; 28418900; 28807012; 29045385; 29045389; 29045831; 29056421; 29166018; 29200206; 29236775; 29249604; 29323787; 29343584; 29416040; 29541367; 29574466; 29616860; 29688809; 29781103; 29795372; 30024656; 30179224; 30182448; 30206189; 30224337; 30546088; 30647135; 30651545; 30679821; 30786932; 30804394; 30834688; 30872372; 30891497; 30905413; 30938820; 31278054; 31502386; 31518603; 31527801; 31597768; 31666375; 31730000; 31801860; 31822558; 31866294; 32064756; 32088087; 32130729; 32302140; 32444465; 32497973; 32802178; 32802195; 32860838; 32929379; 32966862; 33006472; 33040080; 33095475; 33106424; 33157193; 33207738; 33326746; 33460997; 33487632; 33544460; 33664368; 33780361; 33849069; 33856059; 33933455; 33963175; 34331453; 34500587; 34518535; 34553755; 34921745; 7700386; 8078911; 9326587; 9521656; 9699634; 9716411; 9875289; |
| Motif | |
| Gene Encoded By | |
| Mass | 128,302 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |