P21580 (TNAP3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	790 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence 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. 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. Ref.8 Ref.9 Ref.10 Ref.13 Ref.14 Ref.16 Ref.19 Ref.21 Ref.24 Ref.26 Ref.27
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.27
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 process	Apoptosis Inflammatory response Ubl conjugation pathway
Cellular component	Cytoplasm Lysosome Nucleus
Coding sequence diversity	Polymorphism
Domain	Repeat Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Hydrolase Ligase Protease Thiol protease
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Multifunctional enzyme Reference proteome
Gene Ontology (GO)
Biological_process	B-1 B cell homeostasis Inferred from sequence or structural similarity. 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 cascade 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: Compara negative regulation of cyclin-dependent protein serine/threonine kinase activity Inferred from electronic annotation. Source: Compara negative regulation of endothelial cell apoptotic process Inferred from direct assay PubMed 12885753. Source: BHF-UCL negative regulation of inflammatory response Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of interleukin-1 beta production Inferred from electronic annotation. Source: Compara 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: Compara negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway Inferred from electronic annotation. Source: Compara 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 5 signaling pathway Inferred from electronic annotation. Source: Compara 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 oligomerization domain containing signaling pathway Traceable author statement. Source: Reactome positive regulation of hepatocyte proliferation Inferred from electronic annotation. Source: Compara positive regulation of protein catabolic process Inferred from direct assay PubMed 21127049. Source: BHF-UCL 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 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 muramyl dipeptide Inferred from electronic annotation. Source: Compara tolerance induction to lipopolysaccharide Inferred from mutant phenotype PubMed 21220427. Source: BHF-UCL
Cellular_component	centrosome Inferred from direct assay. Source: HPA cytosol Traceable author statement. Source: Reactome lysosome Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay Ref.12. Source: HGNC
Molecular_function	DNA binding Inferred from electronic annotation. Source: UniProtKB-KW cysteine-type endopeptidase inhibitor activity involved in apoptotic process Non-traceable author statement PubMed 12167698. Source: BHF-UCL protein self-association Inferred from direct assay PubMed 15474016PubMed 8797804. 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.14. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
IKBKG	Q9Y6K9	2	EBI-527670,EBI-81279
Ywhah	P68510	3	EBI-527670,EBI-444641	From a different organism.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 790

790

Tumor necrosis factor alpha-induced protein 3

PRO_0000188791

Chain

1 – 439

439

A20p50

PRO_0000418127

Chain

440 – 790

351

A20p37

PRO_0000418128

Regions

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

Region

157 – 159

3

Interaction with ubiquitin Probable

Region

190 – 192

3

Interaction with ubiquitin Probable

Region

224 – 227

4

Interaction with ubiquitin Probable

Region

286 – 356

71

2 X approximate repeats

Region

369 – 775

407

Interaction with TNIP1 By similarity

Region

386 – 453

68

Interaction with RIPK1

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

Sites

Active site

103

1

Nucleophile Ref.27

Active site

256

1

Proton acceptor Probable

Site

439 – 440

2

Cleavage; by MALT1

Amino acid modifications

Modified residue

459

1

Phosphoserine Ref.22

Natural variations

Natural variant

125

1

A → V. Ref.3
Corresponds to variant rs5029941 [ dbSNP | Ensembl ].

VAR_020447

Natural variant

127

1

F → C. Ref.3
Corresponds to variant rs2230926 [ dbSNP | Ensembl ].

VAR_022143

Natural variant

766

1

A → P. Ref.3
Corresponds to variant rs5029957 [ dbSNP | Ensembl ].

VAR_029319

Experimental info

Mutagenesis

70

1

D → A: Minor effect on 'Lys-48' deubiquitinase activity. Strongly reduced 'Lys-63' deubiquitinase activity. Ref.26 Ref.27

Mutagenesis

97

1

T → A: Minor effect on 'Lys-48' deubiquitinase activity. Ref.27

Mutagenesis

100

1

D → A: Strongly reduced deubiquitinase activity. Ref.27

Mutagenesis

103

1

C → A: Loss of deubiquitinase activity. Ref.13 Ref.14 Ref.26 Ref.27

Mutagenesis

103

1

C → S: Loss of 'Lys-63' deubiquitinating activity. Down-regulation of TNF-induced NF-kappa-B activity less effective. Ref.13 Ref.14 Ref.26 Ref.27

Mutagenesis

157

1

L → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.27

Mutagenesis

159

1

Y → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.27

Mutagenesis

190

1

S → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.27

Mutagenesis

192

1

E → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.27

Mutagenesis

224

1

F → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.27

Mutagenesis

227

1

L → A: Strongly reduced 'Lys-48' deubiquitinase activity. Ref.27

Mutagenesis

256

1

H → A: Loss of deubiquitinase activity. Ref.26

Mutagenesis

521

1

C → A: No effect on ubiquitin ligase activity; when associated with A-524. Ref.14

Mutagenesis

524

1

C → A: No effect on ubiquitin ligase activity; when associated with A-521. Ref.14

Mutagenesis

562

1

R → A: Abolishes interactionj with YWHAZ AND YWHAH; no effect on inhibitory activity of TNF-induced NF-kappa-B activation. Ref.9

Mutagenesis

565

1

S → A: Abolishes interactionj with YWHAZ AND YWHAH; no effect on inhibitory activity of TNF-induced NF-kappa-B activation. Ref.9

Mutagenesis

614

1

Y → A: Impairs ubiquitination activity. Loss of down-regulation of NF-kappa-B activity; when associated with A-615 or R-626. Ref.28

Mutagenesis

615

1

F → A: Impairs ubiquitination activity. Loss of down-regulation of NF-kappa-B activity; when associated with A-614. Ref.28

Mutagenesis

624

1

C → A: Marked attenuation of ubiquitin ligase activity and inhibition of RIPK1 degradation; when associated with A-627. Ref.14

Mutagenesis

626

1

L → R: Impairs ubiquitination activity. Loss of down-regulation of NF-kappa-B activity; when associated with A-614. Ref.28

Mutagenesis

627

1

C → A: Marked attenuation of ubiquitin ligase activity and inhibition of RIPK1 degradation; when associated with A-624. Ref.14

Mutagenesis

770 – 771

2

FG → AA: Impairs polyubiquitin binding, abolishes inhibition of IKK activation.

Mutagenesis

779

1

C → A: Impairs polyubiquitin binding, abolishes inhibition of IKK activation; when associated with A-782. Ref.24

Mutagenesis

782

1

C → A: Impairs polyubiquitin binding, abolishes inhibition of IKK activation; when associated with A-779. Ref.24

Secondary structure

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790

Helix Strand Turn

Details...

Helix

10 – 14

5

Helix

15 – 27

13

Beta strand

33 – 36

4

Beta strand

39 – 42

4

Helix

43 – 45

3

Helix

58 – 68

11

Helix

71 – 79

9

Beta strand

82 – 84

3

Beta strand

87 – 89

3

Beta strand

92 – 95

4

Helix

103 – 113

11

Helix

121 – 132

12

Helix

136 – 147

12

Helix

166 – 174

9

Beta strand

176 – 178

3

Beta strand

181 – 185

5

Helix

193 – 202

10

Beta strand

207 – 211

5

Beta strand

231 – 233

3

Helix

240 – 242

3

Beta strand

248 – 252

5

Beta strand

257 – 263

7

Beta strand

265 – 268

4

Beta strand

270 – 278

9

Beta strand

280 – 285

6

Helix

293 – 297

5

Helix

299 – 306

8

Beta strand

309 – 315

7

Beta strand

317 – 320

4

Beta strand

322 – 329

8

Helix

337 – 339

3

Helix

341 – 357

17

Helix

359 – 361

3

Beta strand

384 – 386

3

Turn

398 – 402

5

Helix

405 – 412

8

Beta strand

604 – 606

3

Beta strand

613 – 615

3

Helix

618 – 620

3

Helix

625 – 634

10

Helix

773 – 775

3

Helix

780 – 788

9

Sequences

	Sequence		Length	Mass (Da)
	P21580 [UniParc]. Last modified May 1, 1991. Version 1. Checksum: 320AEA97F58D4491	FASTA	790	89,614
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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, MASS SPECTROMETRY. 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]	"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.
[26]	"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.
[27]	"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.
[28]	"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.

Web resources

SeattleSNPs

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.

IPI

IPI00009448.

PIR

A35797.

RefSeq

NP_001257436.1. NM_001270507.1.
NP_001257437.1. NM_001270508.1.
NP_006281.1. NM_006290.3.

UniGene

Hs.211600.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2EQE	NMR	-	A	597-631	[»]
2EQF	NMR	-	A	758-790	[»]
2EQG	NMR	-	A	381-416	[»]
2VFJ	X-ray	3.20	A/B/C/D	1-366	[»]
3DKB	X-ray	2.50	A/B/C/D/E/F	1-370	[»]
3OJ3	X-ray	2.50	I/J/K/L/M/N/O/P	592-635	[»]
3OJ4	X-ray	3.40	C/F	592-635	[»]
3VUW	X-ray	1.95	E/F/G	757-789	[»]
3VUX	X-ray	1.70	E/F/G	757-790	[»]
3VUY	X-ray	1.98	D/E/F	757-790	[»]
3ZJD	X-ray	1.87	A/B	1-366	[»]
3ZJE	X-ray	1.84	A/B	1-366	[»]
3ZJF	X-ray	2.20	A/B	1-366	[»]
3ZJG	X-ray	1.92	A/B	1-366	[»]

ProteinModelPortal

P21580.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-33804N.

IntAct

P21580. 13 interactions.

MINT

MINT-97330.

STRING

9606.ENSP00000237289.

Protein family/group databases

MEROPS

C64.003.

PTM databases

PhosphoSite

P21580.

Polymorphism databases

DMDM

112894.

Proteomic databases

PaxDb

P21580.

PRIDE

P21580.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000237289; ENSP00000237289; ENSG00000118503.

GeneID

7128.

KEGG

hsa:7128.

UCSC

uc003qhr.3. human.

Organism-specific databases

CTD

7128.

GeneCards

GC06P138188.

HGNC

HGNC:11896. TNFAIP3.

HPA

HPA002116.

MIM

191163. gene.

neXtProt

NX_P21580.

PharmGKB

PA36593.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG248343.

HOGENOM

HOG000133004.

HOVERGEN

HBG059260.

InParanoid

P21580.

KO

K11859.

OMA

CETPNCP.

OrthoDB

EOG4XD3QK.

Enzyme and pathway databases

Pathway_Interaction_DB

nfkappabcanonicalpathway. Canonical NF-kappaB pathway.
tnfpathway. TNF receptor signaling pathway.

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

P21580.

Bgee

P21580.

CleanEx

HS_TNFAIP3.

Genevestigator

P21580.

GermOnline

ENSG00000118503. Homo sapiens.

Family and domain databases

InterPro

IPR003323. OTU.
IPR002653. Znf_A20.
[Graphical view]

Pfam

PF02338. OTU. 1 hit.
PF01754. zf-A20. 6 hits.
[Graphical view]

SMART

SM00259. ZnF_A20. 7 hits.
[Graphical view]

PROSITE

PS50802. OTU. 1 hit.
PS51036. ZF_A20. 7 hits.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

TNFAIP3. human.

EvolutionaryTrace

P21580.

GenomeRNAi

7128.

NextBio

27895.

SOURCE

Search...

Entry information

Entry name

TNAP3_HUMAN

Accession

Primary (citable) accession number: P21580
Secondary accession number(s): B2R767 , E1P588, Q2HIX9, Q5VXQ7, Q9NSR6

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 1, 1991
Last sequence update:	May 1, 1991
Last modified:	May 1, 2013
This is version 137 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.