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Q4R8W3 (TNAP3_MACFA) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 49. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (2) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Tumor necrosis factor alpha-induced protein 3

Short name=TNF alpha-induced protein 3
EC=3.4.19.12
EC=6.3.2.-

Cleaved into the following 2 chains:

  1. A20p50
  2. A20p37
Gene names
Name:TNFAIP3
ORF Names:QtsA-11293
OrganismMacaca fascicularis (Crab-eating macaque) (Cynomolgus monkey)
Taxonomic identifier9541 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniCercopithecidaeCercopithecinaeMacaca

Protein attributes

Sequence length790 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at transcript level

General annotation (Comments)

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 By similarity.

Catalytic activity

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).

Subunit structure

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.

Subcellular location

Cytoplasm By similarity. Nucleus By similarity. Lysosome By similarity.

A20p50: Cytoplasm By similarity.

Domain

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.

Post-translational modification

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.

Sequence similarities

Belongs to the peptidase C64 family.

Contains 7 A20-type zinc fingers.

Contains 1 OTU domain.

Ontologies

Keywords
   Biological processApoptosis
Inflammatory response
Ubl conjugation pathway
   Cellular componentCytoplasm
Lysosome
Nucleus
   DomainRepeat
Zinc-finger
   LigandDNA-binding
Metal-binding
Zinc
   Molecular functionHydrolase
Ligase
Protease
Thiol protease
   PTMAcetylation
Phosphoprotein
   Technical termMultifunctional enzyme
Gene Ontology (GO)
   Biological_processapoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

cellular response to hydrogen peroxide

Inferred from sequence or structural similarity. Source: UniProtKB

inflammatory response

Inferred from electronic annotation. Source: UniProtKB-KW

negative regulation of I-kappaB kinase/NF-kappaB signaling

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of inflammatory response

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of innate immune response

Inferred from sequence or structural similarity. Source: UniProtKB

protein K11-linked deubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

protein K48-linked deubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

protein K48-linked ubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

protein K63-linked deubiquitination

Inferred from sequence or structural similarity. Source: UniProtKB

proteolysis

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentlysosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionDNA binding

Inferred from electronic annotation. Source: UniProtKB-KW

ubiquitin thiolesterase activity

Inferred from sequence or structural similarity. Source: UniProtKB

ubiquitin-protein ligase activity

Inferred from sequence or structural similarity. Source: UniProtKB

ubiquitin-specific protease activity

Inferred from sequence or structural similarity. Source: UniProtKB

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed By similarity
Chain2 – 790789Tumor necrosis factor alpha-induced protein 3
PRO_0000188792
Chain2 – 439438A20p50
PRO_0000418129
Chain440 – 790351A20p37
PRO_0000418130

Regions

Domain92 – 263172OTU
Repeat286 – 317321
Repeat324 – 356332
Zinc finger381 – 41636A20-type 1
Zinc finger472 – 50736A20-type 2
Zinc finger515 – 54834A20-type 3
Zinc finger601 – 63636A20-type 4
Zinc finger651 – 68636A20-type 5
Zinc finger710 – 74536A20-type 6
Zinc finger756 – 79035A20-type 7
Region58 – 300243TRAF-binding By similarity
Region157 – 1593Interaction with ubiquitin By similarity
Region190 – 1923Interaction with ubiquitin By similarity
Region224 – 2274Interaction with ubiquitin By similarity
Region286 – 356712 X approximate repeats
Region369 – 775407Interaction with TNIP1 By similarity
Region386 – 45368Interaction with RIPK1 By similarity
Region605 – 65551Required for proteosomal degradation of UBE2N and UBE2D3, TRAF6 deubiquitination, and TAX1BP1 interaction with UBE2N By similarity
Region606 – 790185Sufficient for inhibitory activity of TNF-induced NF-kappa-B activity By similarity
Region697 – 79094Required for lysosomal localization and for TRAF2 lysosomal degradation By similarity

Sites

Active site1001 By similarity
Active site1031Nucleophile By similarity
Active site2561Proton acceptor By similarity
Site439 – 4402Cleavage; by MALT1 By similarity

Amino acid modifications

Modified residue21N-acetylalanine By similarity
Modified residue4591Phosphoserine By similarity

Sequences

Sequence LengthMass (Da)Tools
Q4R8W3 [UniParc].

Last modified July 19, 2005. Version 1.
Checksum: EF112EDE0D4F40E9

FASTA79089,534
        10         20         30         40         50         60 
MAEQVLPQAL YLSNMRKAVK IRERTPEDIF KPTNGIIHHF KTMHRYTLEM FRTCQFCPQF 

        70         80         90        100        110        120 
REIIHKALID KNIQASLESQ KKLNWCREVR KLVALKTNGD GNCLMHATSQ YMWGVQDTDL 

       130        140        150        160        170        180 
VLRKALFSTL KETDTRNFKF RWQLESLKSQ EFVETGLCYD TRNWNDEWDN LIKMASTDTP 

       190        200        210        220        230        240 
MARSGLQYNS LEEIHIFVLC NILRRPIIVI SDKMLRSLES GSNFAPLKVG GIYLPLHWPA 

       250        260        270        280        290        300 
QECYRYPIVL GYDSHHFVPL VTLKDSGPEI RAVPLVNRDR GRFEDLKVHF LTDPENEMKE 

       310        320        330        340        350        360 
KLLKEYLMVI EIPVQGWDHG TTHLINAAKL DEANLPKEIN LVDDYFELVQ HEYKKWQENS 

       370        380        390        400        410        420 
EQGRSEMHAQ NPMESSLPQL SLMDVKCETP NCPFFMSVNT QPLCHECSER RQKNQNKLPK 

       430        440        450        460        470        480 
LNSKPGPEGL PGMALGASRG EAYEPLAWNP EEPTGGPHSA PPTAPSPFLF SETTAMKCRS 

       490        500        510        520        530        540 
PGCPFTLNVQ HNGFCERCHN ARQLHASHAA DHTRHLDPGK CQACLQDVTR TFNGICSTCF 

       550        560        570        580        590        600 
KRTTAEASSS LSTSLPPSCH QRSKSDPSQL VRSPSPHSCH RAGNDAPAGC LSQAARTPGD 

       610        620        630        640        650        660 
RTGTSKCRKA GCMYFGTPEN KGFCTLCFIE YRENKHLVAA SGKASPTASR FQNTIPCLGR 

       670        680        690        700        710        720 
ECGTLGSTMF EGYCQKCFIE AQNQRFHEAK RTEEQLRSSQ RRDVPRTTQS TSRPKCARAS 

       730        740        750        760        770        780 
CKNILACRSE ELCMECQHPN PRMGPGAHRG EPAPEDPPKQ RCWAPACDHF GNAKCNGYCN 

       790 
ECFQFKQMYG 

« Hide

References

[1]"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].
Tissue: Testis.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AB168334 mRNA. Translation: BAE00458.1.
RefSeqNP_001270745.1. NM_001283816.1.
UniGeneMfa.6768.

3D structure databases

ProteinModelPortalQ4R8W3.
SMRQ4R8W3. Positions 3-362, 382-419, 597-631, 758-790.
ModBaseSearch...
MobiDBSearch...

Protein family/group databases

MEROPSC64.003.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

GeneID101867362.
KEGGmcf:101867362.

Organism-specific databases

CTD7128.

Phylogenomic databases

HOVERGENHBG059260.
KOK11859.

Family and domain databases

InterProIPR003323. OTU.
IPR002653. Znf_A20.
[Graphical view]
PfamPF02338. OTU. 1 hit.
PF01754. zf-A20. 6 hits.
[Graphical view]
SMARTSM00259. ZnF_A20. 7 hits.
[Graphical view]
PROSITEPS50802. OTU. 1 hit.
PS51036. ZF_A20. 7 hits.
[Graphical view]
ProtoNetSearch...

Entry information

Entry nameTNAP3_MACFA
AccessionPrimary (citable) accession number: Q4R8W3
Entry history
Integrated into UniProtKB/Swiss-Prot: January 24, 2006
Last sequence update: July 19, 2005
Last modified: April 16, 2014
This is version 49 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries