Q4R8W3 (TNAP3_MACFA) Reviewed, UniProtKB/Swiss-Prot
Last modified April 3, 2013. Version 41. History...
Names and origin
|Protein names||Recommended name:|
Tumor necrosis factor alpha-induced protein 3
Short name=TNF alpha-induced protein 3
|Organism||Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey)|
|Taxonomic identifier||9541 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Cercopithecidae › Cercopithecinae › Macaca|
|Sequence length||790 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at transcript level|
General annotation (Comments)
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. Deubiquinates 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. Deubiquinates 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 both 'Lys-48'- and 'Lys-63' polyubiquitin chains. Inhibitor of programmed cell death. Has a role in the function of the lymphoid system By similarity.
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).
Homodimer. Interacts with TNIP1, TAX1BP1 and TRAF2. Interacts with RNF11, ITCH and TAX1BP1 only after TNF stimulation; these interaction are transient and they are lost after 1 hour of stimulation with TNF By similarity. Interacts with YWHAZ and YWHAH. Interacts with IKBKG; the interaction is induced by TNF stimulation and by polyubiquitin. Interacts with RIPK1. Interacts with UBE2N; the interaction requires TAX1BP1. Interacts with TRAF6 By similarity.
The A20-type zinc fingers mediate the ubiquitin ligase activity. The A20-type zinc finger 4 selectively recognizes 'Lys-63'-linked polyubiquitin. The A20-type zinc finger 4-7 are sufficient to bind polyubiquitin By similarity.
The OTU domain mediates the deubiquitinase activity By similarity.
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 By similarity.
Belongs to the peptidase C64 family.
Contains 7 A20-type zinc fingers.
Contains 1 OTU domain.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Chain||1 – 790||790||Tumor necrosis factor alpha-induced protein 3||PRO_0000188792|
|Chain||1 – 439||439||A20p50||PRO_0000418129|
|Chain||440 – 790||351||A20p37||PRO_0000418130|
|Domain||92 – 263||172||OTU|
|Repeat||286 – 317||32||1|
|Repeat||324 – 356||33||2|
|Zinc finger||381 – 416||36||A20-type 1|
|Zinc finger||472 – 507||36||A20-type 2|
|Zinc finger||515 – 548||34||A20-type 3|
|Zinc finger||601 – 636||36||A20-type 4|
|Zinc finger||651 – 686||36||A20-type 5|
|Zinc finger||710 – 745||36||A20-type 6|
|Zinc finger||756 – 790||35||A20-type 7|
|Region||58 – 300||243||TRAF-binding By similarity|
|Region||157 – 159||3||Interaction with ubiquitin By similarity|
|Region||190 – 192||3||Interaction with ubiquitin By similarity|
|Region||224 – 227||4||Interaction with ubiquitin By similarity|
|Region||286 – 356||71||2 X approximate repeats|
|Region||369 – 775||407||Interaction with TNIP1 By similarity|
|Region||386 – 453||68||Interaction with RIPK1 By similarity|
|Region||605 – 655||51||Required for proteosomal degradation of UBE2N and UBE2D3, TRAF6 deubiquitination, and TAX1BP1 interaction with UBE2N By similarity|
|Region||606 – 790||185||Sufficient for inhibitory activity of TNF-induced NF-kappa-B activity By similarity|
|Region||697 – 790||94||Required for lysosomal localization and for TRAF2 lysosomal degradation By similarity|
|Active site||103||1||Nucleophile By similarity|
|Active site||256||1||Proton acceptor By similarity|
|Site||439 – 440||2||Cleavage; by MALT1 By similarity|
Amino acid modifications
|Modified residue||459||1||Phosphoserine By similarity|
|||"DNA sequences of macaque genes expressed in brain or testis and its evolutionary implications."|
International consortium for macaque cDNA sequencing and analysis
Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
|AB168334 mRNA. Translation: BAE00458.1.|
3D structure databases
|SMR||Q4R8W3. Positions 3-362, 382-419, 597-631, 758-790. |
Protein family/group databases
Protocols and materials databases
Family and domain databases
|InterPro||IPR003323. OTU. |
|Pfam||PF02338. OTU. 1 hit. |
PF01754. zf-A20. 6 hits.
|SMART||SM00259. ZnF_A20. 7 hits. |
|PROSITE||PS50802. OTU. 1 hit. |
PS51036. ZF_A20. 7 hits.
|Accession||Primary (citable) accession number: Q4R8W3|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|