Q4R8W3 (TNAP3_MACFA) 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.-

Cleaved into the following 2 chains:

1. A20p50
2. A20p37

Gene names

Name:	TNFAIP3
ORF Names:	QtsA-11293

Organism

Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey)

Taxonomic identifier

9541 [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 › Cercopithecoidea › Cercopithecidae › Cercopithecinae › Macaca

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 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. 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.
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 process	Apoptosis Inflammatory response Ubl conjugation pathway
Cellular component	Cytoplasm Lysosome Nucleus
Domain	Repeat Zinc-finger
Ligand	DNA-binding Metal-binding Zinc
Molecular function	Hydrolase Ligase Protease Thiol protease
PTM	Phosphoprotein
Technical term	Multifunctional enzyme
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from electronic annotation. Source: UniProtKB-KW inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of I-kappaB kinase/NF-kappaB cascade 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_component	lysosome Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	DNA 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 key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	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
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 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
Sites
	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

Sequences

	Sequence		Length	Mass (Da)
	Q4R8W3 [UniParc]. Last modified July 19, 2005. Version 1. Checksum: EF112EDE0D4F40E9	FASTA	790	89,534
	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

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.
3D structure databases
ProteinModelPortal	Q4R8W3.
SMR	Q4R8W3. Positions 3-362, 382-419, 597-631, 758-790.
ModBase	Search...
Protein family/group databases
MEROPS	C64.003.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Phylogenomic databases
HOVERGEN	HBG059260.
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...

Entry information

Entry name

TNAP3_MACFA

Accession

Primary (citable) accession number: Q4R8W3

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 24, 2006
Last sequence update:	July 19, 2005
Last modified:	April 3, 2013
This is version 41 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program