| IED ID | IndEnz0002007191 |
| Enzyme Type ID | protease007191 |
| Protein Name |
Ubiquitin carboxyl-terminal hydrolase CYLD EC 3.4.19.12 Deubiquitinating enzyme CYLD Ubiquitin thioesterase CYLD Ubiquitin-specific-processing protease CYLD |
| Gene Name | CYLD CYLD1 KIAA0849 HSPC057 |
| 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 | MSSGLWSQEKVTSPYWEERIFYLLLQECSVTDKQTQKLLKVPKGSIGQYIQDRSVGHSRIPSAKGKKNQIGLKILEQPHAVLFVDEKDVVEINEKFTELLLAITNCEERFSLFKNRNRLSKGLQIDVGCPVKVQLRSGEEKFPGVVRFRGPLLAERTVSGIFFGVELLEEGRGQGFTDGVYQGKQLFQCDEDCGVFVALDKLELIEDDDTALESDYAGPGDTMQVELPPLEINSRVSLKVGETIESGTVIFCDVLPGKESLGYFVGVDMDNPIGNWDGRFDGVQLCSFACVESTILLHINDIIPALSESVTQERRPPKLAFMSRGVGDKGSSSHNKPKATGSTSDPGNRNRSELFYTLNGSSVDSQPQSKSKNTWYIDEVAEDPAKSLTEISTDFDRSSPPLQPPPVNSLTTENRFHSLPFSLTKMPNTNGSIGHSPLSLSAQSVMEELNTAPVQESPPLAMPPGNSHGLEVGSLAEVKENPPFYGVIRWIGQPPGLNEVLAGLELEDECAGCTDGTFRGTRYFTCALKKALFVKLKSCRPDSRFASLQPVSNQIERCNSLAFGGYLSEVVEENTPPKMEKEGLEIMIGKKKGIQGHYNSCYLDSTLFCLFAFSSVLDTVLLRPKEKNDVEYYSETQELLRTEIVNPLRIYGYVCATKIMKLRKILEKVEAASGFTSEEKDPEEFLNILFHHILRVEPLLKIRSAGQKVQDCYFYQIFMEKNEKVGVPTIQQLLEWSFINSNLKFAEAPSCLIIQMPRFGKDFKLFKKIFPSLELNITDLLEDTPRQCRICGGLAMYECRECYDDPDISAGKIKQFCKTCNTQVHLHPKRLNHKYNPVSLPKDLPDWDWRHGCIPCQNMELFAVLCIETSHYVAFVKYGKDDSAWLFFDSMADRDGGQNGFNIPQVTPCPEVGEYLKMSLEDLHSLDSRRIQGCARRLLCDAYMCMYQSPTMSLYK |
| Enzyme Length | 956 |
| Uniprot Accession Number | Q9NQC7 |
| Absorption | |
| Active Site | ACT_SITE 601; /note="Nucleophile"; /evidence="ECO:0000255|PROSITE-ProRule:PRU10092, ECO:0000269|PubMed:18313383"; ACT_SITE 871; /note="Proton acceptor"; /evidence="ECO:0000305|PubMed:18313383" |
| Activity Regulation | ACTIVITY REGULATION: Inhibited by phosphorylation at serine residues. {ECO:0000269|PubMed:15870263}. |
| 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:18313383, ECO:0000269|PubMed:27458237, ECO:0000269|PubMed:27591049, ECO:0000269|PubMed:32185393}; |
| DNA Binding | |
| EC Number | 3.4.19.12 |
| Enzyme Function | FUNCTION: Deubiquitinase that specifically cleaves 'Lys-63'- and linear 'Met-1'-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-alpha-induced necroptosis (PubMed:18636086, PubMed:26670046, PubMed:27458237, PubMed:26997266, PubMed:27591049, PubMed:29291351, PubMed:18313383, PubMed:32185393). Negatively regulates NF-kappa-B activation by deubiquitinating upstream signaling factors (PubMed:12917689, PubMed:12917691, PubMed:32185393). Contributes to the regulation of cell survival, proliferation and differentiation via its effects on NF-kappa-B activation (PubMed:12917690). Negative regulator of Wnt signaling (PubMed:20227366). Inhibits HDAC6 and thereby promotes acetylation of alpha-tubulin and stabilization of microtubules (PubMed:19893491). Plays a role in the regulation of microtubule dynamics, and thereby contributes to the regulation of cell proliferation, cell polarization, cell migration, and angiogenesis (PubMed:18222923, PubMed:20194890). Required for normal cell cycle progress and normal cytokinesis (PubMed:17495026, PubMed:19893491). Inhibits nuclear translocation of NF-kappa-B (PubMed:18636086). Plays a role in the regulation of inflammation and the innate immune response, via its effects on NF-kappa-B activation (PubMed:18636086). Dispensable for the maturation of intrathymic natural killer cells, but required for the continued survival of immature natural killer cells (By similarity). Negatively regulates TNFRSF11A signaling and osteoclastogenesis (By similarity). Involved in the regulation of ciliogenesis, allowing ciliary basal bodies to migrate and dock to the plasma membrane; this process does not depend on NF-kappa-B activation (By similarity). Ability to remove linear ('Met-1'-linked) polyubiquitin chains regulates innate immunity and TNF-alpha-induced necroptosis: recruited to the LUBAC complex via interaction with SPATA2 and restricts linear polyubiquitin formation on target proteins (PubMed:26997266, PubMed:26670046, PubMed:27458237, PubMed:27591049). Regulates innate immunity by restricting linear polyubiquitin formation on RIPK2 in response to NOD2 stimulation (PubMed:26997266). Involved in TNF-alpha-induced necroptosis by removing linear ('Met-1'-linked) polyubiquitin chains from RIPK1, thereby regulating the kinase activity of RIPK1 (By similarity). Negatively regulates intestinal inflammation by removing 'Lys-63' linked polyubiquitin chain of NLRP6, thereby reducing the interaction between NLRP6 and PYCARD/ASC and formation of the NLRP6 inflammasome (By similarity). Removes 'Lys-63' linked polyubiquitin chain of MAP3K7, which inhibits phosphorylation and blocks downstream activation of the JNK-p38 kinase cascades (PubMed:29291351). {ECO:0000250|UniProtKB:Q80TQ2, ECO:0000269|PubMed:12917689, ECO:0000269|PubMed:12917690, ECO:0000269|PubMed:12917691, ECO:0000269|PubMed:17495026, ECO:0000269|PubMed:18222923, ECO:0000269|PubMed:18313383, ECO:0000269|PubMed:18636086, ECO:0000269|PubMed:19893491, ECO:0000269|PubMed:20194890, ECO:0000269|PubMed:20227366, ECO:0000269|PubMed:26670046, ECO:0000269|PubMed:26997266, ECO:0000269|PubMed:27458237, ECO:0000269|PubMed:27591049, ECO:0000269|PubMed:29291351, ECO:0000269|PubMed:32185393}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (2); Alternative sequence (1); Beta strand (40); Chain (1); Compositional bias (1); Domain (4); Erroneous initiation (1); Frameshift (1); Helix (22); Metal binding (8); Modified residue (3); Mutagenesis (18); Natural variant (5); Region (6); Turn (6) |
| Keywords | 3D-structure;Alternative splicing;Amyotrophic lateral sclerosis;Cell cycle;Cell membrane;Cell projection;Cytoplasm;Cytoskeleton;Disease variant;Hydrolase;Immunity;Innate immunity;Membrane;Metal-binding;Microtubule;Neurodegeneration;Phosphoprotein;Protease;Reference proteome;Repeat;Thiol protease;Tumor suppressor;Ubl conjugation;Ubl conjugation pathway;Wnt signaling pathway;Zinc |
| Interact With | O95786; Q9UBN7; Q96J02; Q96J02-2; Q9UM82; Q71U36 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:18313383, ECO:0000269|PubMed:32185393}. Cytoplasm, perinuclear region. Cytoplasm, cytoskeleton. Cell membrane; Peripheral membrane protein; Cytoplasmic side. Cytoplasm, cytoskeleton, microtubule organizing center, centrosome {ECO:0000269|PubMed:25134987}. Cytoplasm, cytoskeleton, spindle {ECO:0000269|PubMed:25134987}. Cytoplasm, cytoskeleton, cilium basal body {ECO:0000250|UniProtKB:Q80TQ2}. Note=Detected at the microtubule cytoskeleton during interphase. Detected at the midbody during telophase. During metaphase, it remains localized to the centrosome but is also present along the spindle (PubMed:25134987). {ECO:0000250|UniProtKB:Q80TQ2, ECO:0000269|PubMed:25134987}. |
| Modified Residue | MOD_RES 387; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:24275569"; MOD_RES 418; /note="Phosphoserine"; /evidence="ECO:0000269|PubMed:15870263, ECO:0007744|PubMed:23186163"; MOD_RES 422; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163" |
| Post Translational Modification | PTM: Ubiquitinated. Polyubiquitinated in hepatocytes treated with palmitic acid. Ubiquitination is mediated by E3 ligase TRIM47 and leads to proteasomal degradation. {ECO:0000269|PubMed:29291351}.; PTM: Phosphorylated on several serine residues by IKKA and/or IKKB in response to immune stimuli. Phosphorylation requires IKBKG. Phosphorylation abolishes TRAF2 deubiquitination, interferes with the activation of Jun kinases, and strongly reduces CD40-dependent gene activation by NF-kappa-B. {ECO:0000269|PubMed:15870263}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (3); X-ray crystallography (2) |
| Cross Reference PDB | 1IXD; 1WHL; 1WHM; 2VHF; 7OWD; |
| Mapped Pubmed ID | 12887920; 15024746; 15226292; 15289313; 15496400; 15620648; 16135788; 16230348; 16260783; 16500080; 16603398; 16627981; 16713561; 16774947; 16953224; 17606441; 17608805; 17609426; 17662085; 17851586; 17875891; 17925880; 17981138; 18178551; 18234730; 18242958; 18245814; 18332137; 18363762; 18467330; 18497946; 18977328; 19076795; 19373254; 19462465; 19481526; 19615732; 19800320; 19807742; 19910467; 19911186; 19913121; 19917957; 19951577; 20151946; 20347313; 20414373; 20502185; 20593489; 20628086; 20711500; 20797623; 20832754; 20838385; 20854080; 20972631; 21389835; 21408173; 21420166; 21478324; 21498625; 21552290; 21577203; 21605102; 21718647; 21900959; 21931648; 21988832; 22017589; 22037414; 22049921; 22057290; 22077640; 22157808; 22179575; 22297296; 22362744; 22435550; 22469839; 22491319; 22689134; 22848449; 22895009; 23002441; 23171463; 23300340; 23313255; 23404581; 23567228; 23575688; 23584127; 23641715; 23694822; 23725390; 23754495; 23832602; 23861985; 23879700; 24092863; 24098568; 24104553; 24247569; 24255178; 24261740; 24398777; 24461064; 24469800; 24552808; 24577083; 24614225; 24867235; 24961988; 25117167; 25130432; 25234269; 25329885; 25347032; 25389768; 25501176; 25565632; 25641919; 25751345; 25782638; 25824771; 25923723; 25935309; 26056944; 26271973; 26329847; 26370355; 26638075; 26711782; 26717101; 26719415; 26861065; 27189061; 27357419; 27391066; 27448305; 27570065; 27681433; 27738385; 28184924; 28295222; 28534976; 28566736; 28572092; 28629782; 28840581; 28901464; 29054757; 29166644; 29235674; 29463883; 29478249; 29755980; 29807073; 29808164; 29974194; 30132887; 30269739; 30285829; 30362575; 30542706; 30554661; 31067453; 31101826; 31366726; 31406156; 31624251; 31635163; 31833565; 31860169; 31885317; 32024820; 32418059; 32441799; 32602581; 32678957; 32705175; 32738418; 32783365; 32862616; 32892208; 32901872; 33031450; 33031609; 33378022; 33507567; 33545631; 33629796; 34497368; 34610306; 34742871; |
| Motif | |
| Gene Encoded By | |
| Mass | 107,316 |
| Kinetics | |
| Metal Binding | METAL 788; /note=Zinc 1; /evidence=ECO:0000269|PubMed:18313383; METAL 791; /note=Zinc 1; /evidence=ECO:0000269|PubMed:18313383; METAL 799; /note=Zinc 2; /evidence=ECO:0000269|PubMed:18313383; METAL 802; /note=Zinc 2; /evidence=ECO:0000269|PubMed:18313383; METAL 817; /note=Zinc 1; /evidence=ECO:0000269|PubMed:18313383; METAL 820; /note=Zinc 1; /evidence=ECO:0000269|PubMed:18313383; METAL 825; /note=Zinc 2; /evidence=ECO:0000269|PubMed:18313383; METAL 833; /note=Zinc 2; /evidence=ECO:0000269|PubMed:18313383 |
| Rhea ID | |
| Cross Reference Brenda |