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P21580 (TNAP3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 147. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·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.-
Alternative name(s):
OTU domain-containing protein 7C
Putative DNA-binding protein A20
Zinc finger protein A20

Cleaved into the following 2 chains:

  1. A20p50
  2. A20p37
Gene names
Name:TNFAIP3
Synonyms:OTUD7C
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length790 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein 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. Ref.8 Ref.9 Ref.10 Ref.13 Ref.14 Ref.16 Ref.19 Ref.21 Ref.24 Ref.26 Ref.28 Ref.29

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). Ref.26 Ref.28 Ref.29

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; the interaction is inhibited by HTLV-1 protein Tax. Ref.8 Ref.9 Ref.10 Ref.11 Ref.16 Ref.20 Ref.24

Subcellular location

Cytoplasm Ref.12 Ref.19 Ref.23. Nucleus. Lysosome Ref.12 Ref.19 Ref.23.

A20p50: Cytoplasm Ref.12 Ref.19 Ref.23.

Induction

By TNF.

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. Ref.14

The OTU domain mediates the deubiquitinase activity. Ref.14

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. Ref.17 Ref.23

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
   Coding sequence diversityPolymorphism
   DomainRepeat
Zinc-finger
   LigandDNA-binding
Metal-binding
Zinc
   Molecular functionHydrolase
Ligase
Protease
Thiol protease
   PTMAcetylation
Phosphoprotein
   Technical term3D-structure
Complete proteome
Multifunctional enzyme
Reference proteome
Gene Ontology (GO)
   Biological_processB-1 B cell homeostasis

Inferred from sequence or structural similarity. Source: BHF-UCL

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

cellular response to hydrogen peroxide

Inferred from sequence or structural similarity. Source: UniProtKB

cellular response to lipopolysaccharide

Inferred from direct assay PubMed 19912257PubMed 21127049PubMed 21220427. Source: BHF-UCL

inflammatory response

Inferred from electronic annotation. Source: UniProtKB-KW

innate immune response

Traceable author statement. Source: Reactome

negative regulation of B cell activation

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of CD40 signaling pathway

Inferred from mutant phenotype PubMed 12885753. Source: BHF-UCL

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

Inferred from direct assay Ref.14. Source: UniProtKB

negative regulation of NF-kappaB transcription factor activity

Inferred from direct assay Ref.17. Source: BHF-UCL

negative regulation of bone resorption

Non-traceable author statement PubMed 21127049. Source: BHF-UCL

negative regulation of chronic inflammatory response

Inferred from electronic annotation. Source: Ensembl

negative regulation of cyclin-dependent protein serine/threonine kinase activity

Inferred from electronic annotation. Source: Ensembl

negative regulation of endothelial cell apoptotic process

Inferred from direct assay PubMed 12885753. Source: BHF-UCL

negative regulation of extrinsic apoptotic signaling pathway via death domain receptors

Inferred from direct assay PubMed 12167698. Source: BHF-UCL

negative regulation of inflammatory response

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of innate immune response

Inferred from sequence or structural similarity. Source: UniProtKB

negative regulation of interleukin-1 beta production

Inferred from electronic annotation. Source: Ensembl

negative regulation of interleukin-2 production

Inferred from mutant phenotype Ref.17. Source: BHF-UCL

negative regulation of interleukin-6 production

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of osteoclast proliferation

Non-traceable author statement PubMed 21127049. Source: BHF-UCL

negative regulation of protein ubiquitination

Inferred from direct assay PubMed 20392859. Source: BHF-UCL

negative regulation of smooth muscle cell proliferation

Inferred from direct assay PubMed 16816117. Source: BHF-UCL

negative regulation of toll-like receptor 2 signaling pathway

Non-traceable author statement PubMed 15142865. Source: BHF-UCL

negative regulation of toll-like receptor 3 signaling pathway

Inferred from direct assay PubMed 15474016. Source: BHF-UCL

negative regulation of toll-like receptor 4 signaling pathway

Non-traceable author statement PubMed 15142865. Source: BHF-UCL

negative regulation of toll-like receptor 5 signaling pathway

Inferred from electronic annotation. Source: Ensembl

negative regulation of tumor necrosis factor production

Inferred from sequence or structural similarity. Source: BHF-UCL

negative regulation of type I interferon production

Traceable author statement. Source: Reactome

nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway

Traceable author statement. Source: Reactome

nucleotide-binding oligomerization domain containing signaling pathway

Traceable author statement. Source: Reactome

positive regulation of hepatocyte proliferation

Inferred from electronic annotation. Source: Ensembl

positive regulation of protein catabolic process

Inferred from direct assay PubMed 21127049. Source: BHF-UCL

protein K11-linked deubiquitination

Inferred from direct assay Ref.26. Source: UniProtKB

protein K48-linked deubiquitination

Inferred from direct assay Ref.26. Source: UniProtKB

protein K48-linked ubiquitination

Inferred from direct assay Ref.14. Source: UniProtKB

protein K63-linked deubiquitination

Inferred from direct assay Ref.14. Source: UniProtKB

protein deubiquitination

Traceable author statement PubMed 20392859. Source: BHF-UCL

protein oligomerization

Non-traceable author statement PubMed 15474016. Source: BHF-UCL

proteolysis

Inferred from electronic annotation. Source: UniProtKB-KW

regulation of defense response to virus by host

Non-traceable author statement PubMed 15142865. Source: BHF-UCL

regulation of germinal center formation

Inferred from sequence or structural similarity. Source: BHF-UCL

regulation of vascular wound healing

Non-traceable author statement PubMed 16816117. Source: BHF-UCL

response to molecule of bacterial origin

Inferred from direct assay PubMed 19912257. Source: BHF-UCL

response to muramyl dipeptide

Inferred from electronic annotation. Source: Ensembl

tolerance induction to lipopolysaccharide

Inferred from mutant phenotype PubMed 21220427. Source: BHF-UCL

   Cellular_componentcentrosome

Inferred from direct assay. Source: HPA

cytoplasm

Inferred from direct assay. Source: HPA

cytosol

Traceable author statement. Source: Reactome

extracellular vesicular exosome

Inferred from direct assay PubMed 20458337. Source: UniProt

lysosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

nucleus

Inferred from direct assay Ref.12. Source: HGNC

   Molecular_functionDNA binding

Inferred from electronic annotation. Source: UniProtKB-KW

protease binding

Inferred from physical interaction Ref.17. Source: BHF-UCL

protein self-association

Inferred from direct assay PubMed 15474016PubMed 8797804. Source: BHF-UCL

ubiquitin binding

Inferred from physical interaction PubMed 19285159. Source: BHF-UCL

ubiquitin thiolesterase activity

Inferred from mutant phenotype Ref.14. Source: UniProtKB

ubiquitin-protein ligase activity

Inferred from direct assay Ref.14. Source: UniProtKB

ubiquitin-specific protease activity

Inferred from direct assay Ref.14Ref.26. Source: UniProtKB

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Binary interactions

With

Entry

#Exp.

IntAct

Notes

IKBKGQ9Y6K94EBI-527670,EBI-81279
RNF11Q9Y3C52EBI-527670,EBI-396669
YwhahP685103EBI-527670,EBI-444641From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Initiator methionine11Removed Ref.25
Chain2 – 790789Tumor necrosis factor alpha-induced protein 3
PRO_0000188791
Chain2 – 439438A20p50
PRO_0000418127
Chain440 – 790351A20p37
PRO_0000418128

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
Region157 – 1593Interaction with ubiquitin Probable
Region190 – 1923Interaction with ubiquitin Probable
Region224 – 2274Interaction with ubiquitin Probable
Region286 – 356712 X approximate repeats
Region369 – 775407Interaction with TNIP1 By similarity
Region386 – 45368Interaction with RIPK1
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

Sites

Active site1001 By similarity
Active site1031Nucleophile Ref.29
Active site2561Proton acceptor Probable
Site439 – 4402Cleavage; by MALT1

Amino acid modifications

Modified residue21N-acetylalanine Ref.25
Modified residue4591Phosphoserine Ref.22

Natural variations

Natural variant1251A → V. Ref.3
Corresponds to variant rs5029941 [ dbSNP | Ensembl ].
VAR_020447
Natural variant1271F → C. Ref.3
Corresponds to variant rs2230926 [ dbSNP | Ensembl ].
VAR_022143
Natural variant7661A → P. Ref.3
Corresponds to variant rs5029957 [ dbSNP | Ensembl ].
VAR_029319

Experimental info

Mutagenesis701D → A: Minor effect on 'Lys-48' deubiquitinase activity. Strongly reduced 'Lys-63' deubiquitinase activity. Ref.28 Ref.29
Mutagenesis971T → A: Minor effect on 'Lys-48' deubiquitinase activity. Ref.29
Mutagenesis1001D → A: Strongly reduced deubiquitinase activity. Ref.29
Mutagenesis1031C → A: Loss of deubiquitinase activity. Ref.13 Ref.14 Ref.28 Ref.29
Mutagenesis1031C → S: Loss of 'Lys-63' deubiquitinating activity. Down-regulation of TNF-induced NF-kappa-B activity less effective. Ref.13 Ref.14 Ref.28 Ref.29
Mutagenesis1571L → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.29
Mutagenesis1591Y → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.29
Mutagenesis1901S → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.29
Mutagenesis1921E → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.29
Mutagenesis2241F → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.29
Mutagenesis2271L → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.29
Mutagenesis2561H → A: Loss of deubiquitinase activity. Ref.28
Mutagenesis5211C → A: No effect on ubiquitin ligase activity; when associated with A-524. Ref.14
Mutagenesis5241C → A: No effect on ubiquitin ligase activity; when associated with A-521. Ref.14
Mutagenesis5621R → A: Abolishes interactionj with YWHAZ AND YWHAH; no effect on inhibitory activity of TNF-induced NF-kappa-B activation. Ref.9
Mutagenesis5651S → A: Abolishes interactionj with YWHAZ AND YWHAH; no effect on inhibitory activity of TNF-induced NF-kappa-B activation. Ref.9
Mutagenesis6141Y → A: Impairs ubiquitination activity. Loss of down-regulation of NF-kappa-B activity; when associated with A-615 or R-626. Ref.30
Mutagenesis6151F → A: Impairs ubiquitination activity. Loss of down-regulation of NF-kappa-B activity; when associated with A-614. Ref.30
Mutagenesis6241C → A: Marked attenuation of ubiquitin ligase activity and inhibition of RIPK1 degradation; when associated with A-627. Ref.14
Mutagenesis6261L → R: Impairs ubiquitination activity. Loss of down-regulation of NF-kappa-B activity; when associated with A-614. Ref.30
Mutagenesis6271C → A: Marked attenuation of ubiquitin ligase activity and inhibition of RIPK1 degradation; when associated with A-624. Ref.14
Mutagenesis770 – 7712FG → AA: Impairs polyubiquitin binding, abolishes inhibition of IKK activation.
Mutagenesis7791C → A: Impairs polyubiquitin binding, abolishes inhibition of IKK activation; when associated with A-782. Ref.24
Mutagenesis7821C → A: Impairs polyubiquitin binding, abolishes inhibition of IKK activation; when associated with A-779. Ref.24

Secondary structure

.................................................................................... 790
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P21580 [UniParc].

Last modified May 1, 1991. Version 1.
Checksum: 320AEA97F58D4491

FASTA79089,614
        10         20         30         40         50         60 
MAEQVLPQAL YLSNMRKAVK IRERTPEDIF KPTNGIIHHF KTMHRYTLEM FRTCQFCPQF 

        70         80         90        100        110        120 
REIIHKALID RNIQATLESQ 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 
EQGRREGHAQ NPMEPSVPQL SLMDVKCETP NCPFFMSVNT QPLCHECSER RQKNQNKLPK 

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

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

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

       610        620        630        640        650        660 
RTGTSKCRKA GCVYFGTPEN KGFCTLCFIE YRENKHFAAA SGKVSPTASR FQNTIPCLGR 

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

       730        740        750        760        770        780 
CKNILACRSE ELCMECQHPN QRMGPGAHRG EPAPEDPPKQ RCRAPACDHF GNAKCNGYCN 

       790 
ECFQFKQMYG 

« Hide

References

« Hide 'large scale' references
[1]"The A20 cDNA induced by tumor necrosis factor alpha encodes a novel type of zinc finger protein."
Opipari A.W. Jr., Boguski M.S., Dixit V.M.
J. Biol. Chem. 265:14705-14708(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]"Complete sequencing and characterization of 21,243 full-length human cDNAs."
Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. expand/collapse author list , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.
Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Trachea.
[3]SeattleSNPs variation discovery resource
Submitted (MAR-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS VAL-125; CYS-127 AND PRO-766.
[4]"The DNA sequence and analysis of human chromosome 6."
Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]"The full-ORF clone resource of the German cDNA consortium."
Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., Wiemann S., Schupp I.
BMC Genomics 8:399-399(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 155-790.
Tissue: Testis.
[8]"The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation."
Song H.Y., Rothe M., Goeddel D.V.
Proc. Natl. Acad. Sci. U.S.A. 93:6721-6725(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TRAF1 AND TRAF2.
[9]"A20 inhibits NF-kappaB activation independently of binding to 14-3-3 proteins."
De Valck D., Heyninck K., Van Criekinge W., Vandenabeele P., Fiers W., Beyaert R.
Biochem. Biophys. Res. Commun. 238:590-594(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH YWHAZ AND YWHAH, MUTAGENESIS OF ARG-562 AND SER-565.
[10]"Epstein-Barr virus-encoded latent membrane protein 1 activates the JNK pathway through its extreme C-terminus via a mechanism involving TRADD and TRAF2."
Eliopoulos A.G., Blake S.M., Floettmann J.E., Rowe M., Young L.S.
J. Virol. 73:1023-1035(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TRAF2.
[11]"The zinc finger protein A20 interacts with a novel anti-apoptotic protein which is cleaved by specific caspases."
de Valck D., Jin D.-Y., Heyninck K., van de Craen M., Contreras R., Fiers W., Jeang K.-T., Beyaert R.
Oncogene 18:4182-4190(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TAX1BP1.
[12]"Isolation and characterization of two novel A20-like proteins."
Evans P.C., Taylor E.R., Coadwell J., Heyninck K., Beyaert R., Kilshaw P.J.
Biochem. J. 357:617-623(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION.
[13]"Zinc-finger protein A20, a regulator of inflammation and cell survival, has de-ubiquitinating activity."
Evans P.C., Ovaa H., Hamon M., Kilshaw P.J., Hamm S., Bauer S., Ploegh H.L., Smith T.S.
Biochem. J. 378:727-734(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, MUTAGENESIS OF CYS-103.
[14]"De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling."
Wertz I.E., O'Rourke K.M., Zhou H., Eby M., Aravind L., Seshagiri S., Wu P., Wiesmann C., Baker R., Boone D.L., Ma A., Koonin E.V., Dixit V.M.
Nature 430:694-699(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DOMAIN OTU, DOMAIN A20-TYPE ZINC-FINGER, MUTAGENESIS OF CYS-103; CYS-521; CYS-524; CYS-624 AND CYS-627.
[15]"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.
Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[16]"ABIN-1 binds to NEMO/IKKgamma and co-operates with A20 in inhibiting NF-kappaB."
Mauro C., Pacifico F., Lavorgna A., Mellone S., Iannetti A., Acquaviva R., Formisano S., Vito P., Leonardi A.
J. Biol. Chem. 281:18482-18488(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH IKBKG AND TNIP1.
[17]"T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20."
Coornaert B., Baens M., Heyninck K., Bekaert T., Haegman M., Staal J., Sun L., Chen Z.J., Marynen P., Beyaert R.
Nat. Immunol. 9:263-271(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEOLYTIC CLEAVAGE.
[18]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[19]"The zinc finger protein A20 targets TRAF2 to the lysosomes for degradation."
Li L., Soetandyo N., Wang Q., Ye Y.
Biochim. Biophys. Acta 1793:346-353(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION.
[20]"The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-kappaB signalling."
Shembade N., Parvatiyar K., Harhaj N.S., Harhaj E.W.
EMBO J. 28:513-522(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TAX1BP1; RNF11 AND RIPK1.
[21]"A20 negatively regulates T cell receptor signaling to NF-kappaB by cleaving Malt1 ubiquitin chains."
Duwel M., Welteke V., Oeckinghaus A., Baens M., Kloo B., Ferch U., Darnay B.G., Ruland J., Marynen P., Krappmann D.
J. Immunol. 182:7718-7728(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[22]"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K.
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-459, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Leukemic T-cell.
[23]"Cleavage by MALT1 induces cytosolic release of A20."
Malinverni C., Unterreiner A., Staal J., Demeyer A., Galaup M., Luyten M., Beyaert R., Bornancin F.
Biochem. Biophys. Res. Commun. 400:543-547(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: PROTEOLYTIC CLEAVAGE, SUBCELLULAR LOCATION.
[24]"Direct, noncatalytic mechanism of IKK inhibition by A20."
Skaug B., Chen J., Du F., He J., Ma A., Chen Z.J.
Mol. Cell 44:559-571(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH IKBKG, MUTAGENESIS OF 770-PHE-GLY-771; CYS-779 AND CYS-782.
[25]"N-terminal acetylome analyses and functional insights of the N-terminal acetyltransferase NatB."
Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.
Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS], CLEAVAGE OF INITIATOR METHIONINE [LARGE SCALE ANALYSIS].
[26]"OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis."
Mevissen T.E., Hospenthal M.K., Geurink P.P., Elliott P.R., Akutsu M., Arnaudo N., Ekkebus R., Kulathu Y., Wauer T., El Oualid F., Freund S.M., Ovaa H., Komander D.
Cell 154:169-184(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, CATALYTIC ACTIVITY.
[27]"Solution structure of the A20-type zinc finger domains from human tumor necrosis factor, alpha-induced protein 3."
RIKEN structural genomics initiative (RSGI)
Submitted (OCT-2007) to the PDB data bank
Cited for: STRUCTURE BY NMR OF 381-790.
[28]"Structure of the A20 OTU domain and mechanistic insights into deubiquitination."
Komander D., Barford D.
Biochem. J. 409:77-85(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (3.2 ANGSTROMS) OF 1-366, CATALYTIC ACTIVITY, FUNCTION, MUTAGENESIS OF ASP-70; CYS-103 AND HIS-256.
[29]"Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20."
Lin S.C., Chung J.Y., Lamothe B., Rajashankar K., Lu M., Lo Y.C., Lam A.Y., Darnay B.G., Wu H.
J. Mol. Biol. 376:526-540(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 1-370, ACTIVE SITE, CATALYTIC ACTIVITY, FUNCTION, MUTAGENESIS OF ASP-70; THR-97; ASP-100; CYS-103; LEU-157; TYR-159; SER-190; GLU-192; PHE-224 AND LEU-227.
[30]"Ubiquitin binding to A20 ZnF4 is required for modulation of NF-kappaB signaling."
Bosanac I., Wertz I.E., Pan B., Yu C., Kusam S., Lam C., Phu L., Phung Q., Maurer B., Arnott D., Kirkpatrick D.S., Dixit V.M., Hymowitz S.G.
Mol. Cell 40:548-557(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 592-635 IN COMPLEX WITH UBIQUITIN, X-RAY CRYSTALLOGRAPHY (3.4 ANGSTROMS) OF 592-635 IN COMPLEX WITH UBIQUITIN AND UBE2D1, MUTAGENESIS OF TYR-614; PHE-615 AND LEU-626.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M59465 mRNA. Translation: AAA51550.1.
AK312862 mRNA. Translation: BAG35714.1.
AY248754 Genomic DNA. Translation: AAO61093.1.
AL357060 Genomic DNA. Translation: CAH72937.1.
CH471051 Genomic DNA. Translation: EAW47925.1.
CH471051 Genomic DNA. Translation: EAW47926.1.
BC113871 mRNA. Translation: AAI13872.1.
BC114480 mRNA. Translation: AAI14481.1.
AL157444 mRNA. Translation: CAB75664.1.
PIRA35797.
RefSeqNP_001257436.1. NM_001270507.1.
NP_001257437.1. NM_001270508.1.
NP_006281.1. NM_006290.3.
XP_005267176.1. XM_005267119.1.
UniGeneHs.211600.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2EQENMR-A597-631[»]
2EQFNMR-A758-790[»]
2EQGNMR-A381-416[»]
2VFJX-ray3.20A/B/C/D1-366[»]
3DKBX-ray2.50A/B/C/D/E/F1-370[»]
3OJ3X-ray2.50I/J/K/L/M/N/O/P592-635[»]
3OJ4X-ray3.40C/F592-635[»]
3VUWX-ray1.95E/F/G757-789[»]
3VUXX-ray1.70E/F/G757-790[»]
3VUYX-ray1.98D/E/F757-790[»]
3ZJDX-ray1.87A/B1-366[»]
3ZJEX-ray1.84A/B1-366[»]
3ZJFX-ray2.20A/B1-366[»]
3ZJGX-ray1.92A/B1-366[»]
ProteinModelPortalP21580.
SMRP21580. Positions 3-362, 382-419, 475-508, 603-635, 758-790.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid112983. 67 interactions.
DIPDIP-33804N.
IntActP21580. 21 interactions.
MINTMINT-97330.
STRING9606.ENSP00000237289.

Protein family/group databases

MEROPSC64.003.

PTM databases

PhosphoSiteP21580.

Polymorphism databases

DMDM112894.

Proteomic databases

PaxDbP21580.
PRIDEP21580.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000237289; ENSP00000237289; ENSG00000118503.
GeneID7128.
KEGGhsa:7128.
UCSCuc003qhr.4. human.

Organism-specific databases

CTD7128.
GeneCardsGC06P138188.
HGNCHGNC:11896. TNFAIP3.
HPAHPA002116.
MIM191163. gene.
neXtProtNX_P21580.
Orphanet536. Systemic lupus erythematosus.
PharmGKBPA36593.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG248343.
HOGENOMHOG000133004.
HOVERGENHBG059260.
InParanoidP21580.
KOK11859.
OMACETPNCP.
OrthoDBEOG7JHM57.
PhylomeDBP21580.
TreeFamTF323312.

Enzyme and pathway databases

ReactomeREACT_6900. Immune System.
SignaLinkP21580.

Gene expression databases

ArrayExpressP21580.
BgeeP21580.
CleanExHS_TNFAIP3.
GenevestigatorP21580.

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...

Other

ChiTaRSTNFAIP3. human.
EvolutionaryTraceP21580.
GeneWikiTNFAIP3.
GenomeRNAi7128.
NextBio27895.
PROP21580.
SOURCESearch...

Entry information

Entry nameTNAP3_HUMAN
AccessionPrimary (citable) accession number: P21580
Secondary accession number(s): B2R767 expand/collapse secondary AC list , E1P588, Q2HIX9, Q5VXQ7, Q9NSR6
Entry history
Integrated into UniProtKB/Swiss-Prot: May 1, 1991
Last sequence update: May 1, 1991
Last modified: April 16, 2014
This is version 147 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Peptidase families

Classification of peptidase families and list of entries

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 6

Human chromosome 6: entries, gene names and cross-references to MIM