| IED ID | IndEnz0002012478 |
| Enzyme Type ID | protease012478 |
| Protein Name |
Tumor necrosis factor alpha-induced protein 3 TNF alpha-induced protein 3 EC 2.3.2.- EC 3.4.19.12 OTU domain-containing protein 7C Putative DNA-binding protein A20 Zinc finger protein A20 Cleaved into: A20p50; A20p37 |
| Gene Name | TNFAIP3 OTUD7C |
| 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 | MAEQVLPQALYLSNMRKAVKIRERTPEDIFKPTNGIIHHFKTMHRYTLEMFRTCQFCPQFREIIHKALIDRNIQATLESQKKLNWCREVRKLVALKTNGDGNCLMHATSQYMWGVQDTDLVLRKALFSTLKETDTRNFKFRWQLESLKSQEFVETGLCYDTRNWNDEWDNLIKMASTDTPMARSGLQYNSLEEIHIFVLCNILRRPIIVISDKMLRSLESGSNFAPLKVGGIYLPLHWPAQECYRYPIVLGYDSHHFVPLVTLKDSGPEIRAVPLVNRDRGRFEDLKVHFLTDPENEMKEKLLKEYLMVIEIPVQGWDHGTTHLINAAKLDEANLPKEINLVDDYFELVQHEYKKWQENSEQGRREGHAQNPMEPSVPQLSLMDVKCETPNCPFFMSVNTQPLCHECSERRQKNQNKLPKLNSKPGPEGLPGMALGASRGEAYEPLAWNPEESTGGPHSAPPTAPSPFLFSETTAMKCRSPGCPFTLNVQHNGFCERCHNARQLHASHAPDHTRHLDPGKCQACLQDVTRTFNGICSTCFKRTTAEASSSLSTSLPPSCHQRSKSDPSRLVRSPSPHSCHRAGNDAPAGCLSQAARTPGDRTGTSKCRKAGCVYFGTPENKGFCTLCFIEYRENKHFAAASGKVSPTASRFQNTIPCLGRECGTLGSTMFEGYCQKCFIEAQNQRFHEAKRTEEQLRSSQRRDVPRTTQSTSRPKCARASCKNILACRSEELCMECQHPNQRMGPGAHRGEPAPEDPPKQRCRAPACDHFGNAKCNGYCNECFQFKQMYG |
| Enzyme Length | 790 |
| Uniprot Accession Number | P21580 |
| Absorption | |
| Active Site | ACT_SITE 100; /evidence=ECO:0000250; ACT_SITE 103; /note=Nucleophile; /evidence=ECO:0000269|PubMed:18164316; ACT_SITE 256; /note=Proton acceptor; /evidence=ECO:0000305|PubMed:18164316 |
| 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:14748687, ECO:0000269|PubMed:17961127, ECO:0000269|PubMed:18164316, ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:27732584}; |
| DNA Binding | |
| EC Number | 2.3.2.-; 3.4.19.12 |
| Enzyme Function | FUNCTION: Ubiquitin-editing enzyme that contains both ubiquitin ligase and deubiquitinase activities. Involved in immune and inflammatory responses signaled by cytokines, such as TNF-alpha and IL-1 beta, or pathogens via Toll-like receptors (TLRs) through terminating NF-kappa-B activity. Essential component of a ubiquitin-editing protein complex, comprising also RNF11, ITCH and TAX1BP1, that ensures the transient nature of inflammatory signaling pathways. In cooperation with TAX1BP1 promotes disassembly of E2-E3 ubiquitin protein ligase complexes in IL-1R and TNFR-1 pathways; affected are at least E3 ligases TRAF6, TRAF2 and BIRC2, and E2 ubiquitin-conjugating enzymes UBE2N and UBE2D3. In cooperation with TAX1BP1 promotes ubiquitination of UBE2N and proteasomal degradation of UBE2N and UBE2D3. Upon TNF stimulation, deubiquitinates 'Lys-63'-polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains. This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NF-kappa-B. Deubiquitinates TRAF6 probably acting on 'Lys-63'-linked polyubiquitin. Upon T-cell receptor (TCR)-mediated T-cell activation, deubiquitinates 'Lys-63'-polyubiquitin chains on MALT1 thereby mediating disassociation of the CBM (CARD11:BCL10:MALT1) and IKK complexes and preventing sustained IKK activation. Deubiquitinates NEMO/IKBKG; the function is facilitated by TNIP1 and leads to inhibition of NF-kappa-B activation. Upon stimulation by bacterial peptidoglycans, probably deubiquitinates RIPK2. Can also inhibit I-kappa-B-kinase (IKK) through a non-catalytic mechanism which involves polyubiquitin; polyubiquitin promotes association with IKBKG and prevents IKK MAP3K7-mediated phosphorylation. Targets TRAF2 for lysosomal degradation. In vitro able to deubiquitinate 'Lys-11'-, 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system. Required for LPS-induced production of proinflammatory cytokines and IFN beta in LPS-tolerized macrophages. {ECO:0000269|PubMed:14748687, ECO:0000269|PubMed:15258597, ECO:0000269|PubMed:16684768, ECO:0000269|PubMed:17961127, ECO:0000269|PubMed:18164316, ECO:0000269|PubMed:18952128, ECO:0000269|PubMed:19494296, ECO:0000269|PubMed:22099304, ECO:0000269|PubMed:23827681, ECO:0000269|PubMed:8692885, ECO:0000269|PubMed:9299557, ECO:0000269|PubMed:9882303}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Active site (3); Beta strand (22); Chain (3); Compositional bias (1); Domain (1); Helix (22); Initiator methionine (1); Metal binding (28); Modified residue (4); Mutagenesis (25); Natural variant (4); Region (14); Site (1); Turn (2); Zinc finger (7) |
| Keywords | 3D-structure;Acetylation;Apoptosis;Cytoplasm;DNA-binding;Disease variant;Hydrolase;Inflammatory response;Lysosome;Metal-binding;Multifunctional enzyme;Nucleus;Phosphoprotein;Protease;Reference proteome;Repeat;Thiol protease;Transferase;Ubl conjugation pathway;Zinc;Zinc-finger |
| Interact With | Q96B67; Q14790; O95995; Q9Y6K9; Q8TBB1; Q4G0R1; P54725; Q9Y3C5; Q9NWF9; Q86VP1; Itself; Q15025; Q8NFZ5; Q96KP6; Q12933; P36406; P68510 |
| Induction | INDUCTION: By TNF. |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Lysosome.; SUBCELLULAR LOCATION: [A20p50]: Cytoplasm. |
| Modified Residue | MOD_RES 2; /note=N-acetylalanine; /evidence=ECO:0007744|PubMed:22814378; MOD_RES 459; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:19690332; MOD_RES 575; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:24275569; MOD_RES 645; /note=Phosphoserine; /evidence=ECO:0007744|PubMed:23186163 |
| Post Translational Modification | PTM: Proteolytically cleaved by MALT1 upon TCR stimulation; disrupts NF-kappa-B inhibitory function and results in increased IL-2 production. It is proposed that only a fraction of TNFAIP3 colocalized with TCR and CBM complex is cleaved, leaving the main TNFAIP3 pool intact. {ECO:0000269|PubMed:18223652, ECO:0000269|PubMed:20804738}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (3); X-ray crystallography (14) |
| Cross Reference PDB | 2EQE; 2EQF; 2EQG; 2VFJ; 3DKB; 3OJ3; 3OJ4; 3VUW; 3VUX; 3VUY; 3ZJD; 3ZJE; 3ZJF; 3ZJG; 5LRX; 5V3B; 5V3P; |
| Mapped Pubmed ID | 10385526; 11389905; 12167698; 12794157; 12887920; 14754897; 15142865; 15169888; 15231748; 15251990; 15334086; 15474016; 15661910; 15862966; 16164629; 16260783; 16306043; 16474993; 16603398; 16816117; 16824518; 16936197; 16953224; 17259397; 17297453; 17886247; 17953374; 17962196; 17982456; 18079694; 18178551; 18794853; 18813897; 18814951; 19110536; 19124729; 19152111; 19165918; 19165919; 19169254; 19240061; 19258598; 19262574; 19292917; 19336370; 19344623; 19366996; 19373254; 19380636; 19380639; 19387456; 19412163; 19445664; 19464428; 19492975; 19565500; 19608751; 19617629; 19643665; 19648161; 19774492; 19838193; 19851077; 19879194; 19902201; 19907439; 19910467; 19912257; 19913121; 19948975; 20032510; 20049410; 20112363; 20176734; 20185725; 20186265; 20190752; 20231195; 20304918; 20353580; 20392859; 20430393; 20439292; 20444755; 20448643; 20483768; 20511617; 20533286; 20585109; 20617138; 20628086; 20628624; 20669229; 20711500; 20800603; 20822710; 20849588; 20852893; 20921970; 20936779; 20962850; 21048031; 21111841; 21208380; 21220427; 21266526; 21326317; 21336280; 21406721; 21437236; 21531730; 21566404; 21604024; 21625233; 21740805; 21763284; 21787353; 21795344; 21885437; 21964925; 21968712; 21988832; 22019834; 22031828; 22087647; 22093807; 22127930; 22179575; 22207688; 22285182; 22402800; 22435550; 22461193; 22488580; 22525270; 22586175; 22623711; 22634524; 22843550; 22848449; 22898832; 22924496; 22925894; 22936803; 22939624; 23002441; 23018911; 23032186; 23032187; 23039325; 23054742; 23114873; 23148088; 23161053; 23164641; 23249958; 23313255; 23418597; 23425151; 23463012; 23463983; 23555688; 23609450; 23635951; 23671587; 23884832; 23901138; 24008839; 24023622; 24028082; 24039598; 24055365; 24091983; 24098568; 24099634; 24159176; 24219294; 24246475; 24357803; 24489017; 24489933; 24500711; 24595242; 24611736; 24713261; 24798189; 24852325; 24871655; 24884566; 24901050; 24953694; 24965710; 24971370; 25024217; 25034154; 25050625; 25190567; 25217635; 25230785; 25264125; 25302371; 25337792; 25354935; 25384343; 25406098; 25416956; 25451900; 25496073; 25631139; 25674272; 25683052; 25684197; 25806576; 25856582; 25890346; 25911380; 25956706; 25993287; 26005883; 26107748; 26143186; 26159495; 26199174; 26338037; 26339029; 26367773; 26382585; 26426612; 26437781; 26474180; 26485275; 26518771; 26598072; 26652732; 26679293; 26716984; 26724675; 26738398; 26758190; 26802121; 26846592; 26909601; 26936212; 26996111; 27072986; 27183919; 27349720; 27371733; 27435953; 27451268; 27529070; 27634895; 27637078; 27640899; 27716397; 27726311; 27779104; 27799070; 27825134; 27845235; 27914808; 27919278; 27986908; 27991929; 28152507; 28189285; 28197630; 28199970; 28251449; 28337659; 28461114; 28473659; 28502291; 28514294; 28569771; 28629782; 28658319; 28682481; 28784141; 28791391; 28888761; 28888782; 28892081; 28911210; 28923245; 28988144; 29067462; 29175508; 29227477; 29233925; 29241730; 29327472; 29343543; 29380463; 29463935; 29486471; 29505600; 29678181; 29696068; 29699987; 29760065; 29776374; 29783072; 29788367; 29789522; 29807108; 29853534; 29940800; 30041578; 30111373; 30118730; 30166590; 30209212; 30301877; 30328471; 30336268; 30485838; 30529365; 30538044; 30543901; 30662920; 30738453; 30760622; 31030956; 31086261; 31120955; 31138864; 31153693; 31160087; 31164164; 31206174; 31300459; 31308453; 31337730; 31381928; 31534238; 31534975; 31581152; 31587140; 31625129; 31783001; 31872456; 32012328; 32015333; 32027437; 32028675; 32038615; 32169275; 32218782; 32280718; 32285140; 32299816; 32334614; 32398022; 32488768; 32514655; 32709905; 32719680; 32798389; 32808859; 32951573; 32968045; 33154446; 33226960; 33241420; 33287909; 33298620; 33515562; 33517278; 33549125; 33549127; 33554442; 33613524; 33677390; 33887878; 33975174; 34137843; 34233950; 34416243; 34781747; |
| Motif | |
| Gene Encoded By | |
| Mass | 89,614 |
| Kinetics | |
| Metal Binding | METAL 387; /note=Zinc 1; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 392; /note=Zinc 1; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 404; /note=Zinc 1; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 407; /note=Zinc 1; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 478; /note=Zinc 2; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 483; /note=Zinc 2; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 495; /note=Zinc 2; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 498; /note=Zinc 2; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 521; /note=Zinc 3; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 524; /note=Zinc 3; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 536; /note=Zinc 3; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 539; /note=Zinc 3; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 607; /note=Zinc 4; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 612; /note=Zinc 4; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 624; /note=Zinc 4; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 627; /note=Zinc 4; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 657; /note=Zinc 5; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 662; /note=Zinc 5; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 674; /note=Zinc 5; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 677; /note=Zinc 5; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 716; /note=Zinc 6; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 721; /note=Zinc 6; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 733; /note=Zinc 6; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 736; /note=Zinc 6; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 762; /note=Zinc 7; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 767; /note=Zinc 7; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 779; /note=Zinc 7; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451; METAL 782; /note=Zinc 7; /evidence=ECO:0000255|PROSITE-ProRule:PRU00451 |
| Rhea ID | |
| Cross Reference Brenda |