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Q4R8W3

- TNAP3_MACFA

UniProt

Q4R8W3 - TNAP3_MACFA

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Protein

Tumor necrosis factor alpha-induced protein 3

Gene
TNFAIP3, QtsA-11293
Organism
Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at transcript leveli

Functioni

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 activityi

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).

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Active sitei100 – 1001 By similarity
Active sitei103 – 1031Nucleophile By similarity
Active sitei256 – 2561Proton acceptor By similarity
Sitei439 – 4402Cleavage; by MALT1 By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri381 – 41636A20-type 1Add
BLAST
Zinc fingeri472 – 50736A20-type 2Add
BLAST
Zinc fingeri515 – 54834A20-type 3Add
BLAST
Zinc fingeri601 – 63636A20-type 4Add
BLAST
Zinc fingeri651 – 68636A20-type 5Add
BLAST
Zinc fingeri710 – 74536A20-type 6Add
BLAST
Zinc fingeri756 – 79035A20-type 7Add
BLAST

GO - Molecular functioni

  1. DNA binding Source: UniProtKB-KW
  2. ligase activity Source: UniProtKB-KW
  3. ubiquitin-protein transferase activity Source: UniProtKB
  4. ubiquitin-specific protease activity Source: UniProtKB
  5. ubiquitin thiolesterase activity Source: UniProtKB
  6. zinc ion binding Source: InterPro

GO - Biological processi

  1. apoptotic process Source: UniProtKB-KW
  2. cellular response to hydrogen peroxide Source: UniProtKB
  3. inflammatory response Source: UniProtKB-KW
  4. negative regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
  5. negative regulation of inflammatory response Source: UniProtKB
  6. negative regulation of innate immune response Source: UniProtKB
  7. protein K11-linked deubiquitination Source: UniProtKB
  8. protein K48-linked deubiquitination Source: UniProtKB
  9. protein K48-linked ubiquitination Source: UniProtKB
  10. protein K63-linked deubiquitination Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Hydrolase, Ligase, Protease, Thiol protease

Keywords - Biological processi

Apoptosis, Inflammatory response, Ubl conjugation pathway

Keywords - Ligandi

DNA-binding, Metal-binding, Zinc

Protein family/group databases

MEROPSiC64.003.

Names & Taxonomyi

Protein namesi
Recommended name:
Tumor necrosis factor alpha-induced protein 3 (EC:3.4.19.12, EC:6.3.2.-)
Short name:
TNF alpha-induced protein 3
Cleaved into the following 2 chains:
Gene namesi
Name:TNFAIP3
ORF Names:QtsA-11293
OrganismiMacaca fascicularis (Crab-eating macaque) (Cynomolgus monkey)
Taxonomic identifieri9541 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniCercopithecidaeCercopithecinaeMacaca

Subcellular locationi

Cytoplasm By similarity. Nucleus By similarity. Lysosome By similarity
Chain A20p50 : Cytoplasm By similarity

GO - Cellular componenti

  1. lysosome Source: UniProtKB-SubCell
  2. nucleus Source: UniProtKB-SubCell
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Lysosome, Nucleus

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed By similarity
Chaini2 – 790789Tumor necrosis factor alpha-induced protein 3PRO_0000188792Add
BLAST
Chaini2 – 439438A20p50PRO_0000418129Add
BLAST
Chaini440 – 790351A20p37PRO_0000418130Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylalanine By similarity
Modified residuei459 – 4591Phosphoserine By similarity

Post-translational modificationi

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.

Keywords - PTMi

Acetylation, Phosphoprotein

Interactioni

Subunit structurei

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.

Structurei

3D structure databases

ProteinModelPortaliQ4R8W3.
SMRiQ4R8W3. Positions 3-362, 382-419, 597-631, 758-790.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini92 – 263172OTUAdd
BLAST
Repeati286 – 317321Add
BLAST
Repeati324 – 356332Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni58 – 300243TRAF-binding By similarityAdd
BLAST
Regioni157 – 1593Interaction with ubiquitin By similarity
Regioni190 – 1923Interaction with ubiquitin By similarity
Regioni224 – 2274Interaction with ubiquitin By similarity
Regioni286 – 356712 X approximate repeatsAdd
BLAST
Regioni369 – 775407Interaction with TNIP1 By similarityAdd
BLAST
Regioni386 – 45368Interaction with RIPK1 By similarityAdd
BLAST
Regioni605 – 65551Required for proteosomal degradation of UBE2N and UBE2D3, TRAF6 deubiquitination, and TAX1BP1 interaction with UBE2N By similarityAdd
BLAST
Regioni606 – 790185Sufficient for inhibitory activity of TNF-induced NF-kappa-B activity By similarityAdd
BLAST
Regioni697 – 79094Required for lysosomal localization and for TRAF2 lysosomal degradation By similarityAdd
BLAST

Domaini

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.

Sequence similaritiesi

Belongs to the peptidase C64 family.
Contains 1 OTU domain.

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

HOVERGENiHBG059260.
KOiK11859.

Family and domain databases

InterProiIPR003323. OTU.
IPR002653. Znf_A20.
[Graphical view]
PfamiPF02338. OTU. 1 hit.
PF01754. zf-A20. 6 hits.
[Graphical view]
SMARTiSM00259. ZnF_A20. 7 hits.
[Graphical view]
PROSITEiPS50802. OTU. 1 hit.
PS51036. ZF_A20. 7 hits.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

Q4R8W3-1 [UniParc]FASTAAdd to Basket

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MAEQVLPQAL YLSNMRKAVK IRERTPEDIF KPTNGIIHHF KTMHRYTLEM    50
FRTCQFCPQF REIIHKALID KNIQASLESQ KKLNWCREVR KLVALKTNGD 100
GNCLMHATSQ YMWGVQDTDL VLRKALFSTL KETDTRNFKF RWQLESLKSQ 150
EFVETGLCYD TRNWNDEWDN LIKMASTDTP MARSGLQYNS LEEIHIFVLC 200
NILRRPIIVI SDKMLRSLES GSNFAPLKVG GIYLPLHWPA QECYRYPIVL 250
GYDSHHFVPL VTLKDSGPEI RAVPLVNRDR GRFEDLKVHF LTDPENEMKE 300
KLLKEYLMVI EIPVQGWDHG TTHLINAAKL DEANLPKEIN LVDDYFELVQ 350
HEYKKWQENS EQGRSEMHAQ NPMESSLPQL SLMDVKCETP NCPFFMSVNT 400
QPLCHECSER RQKNQNKLPK LNSKPGPEGL PGMALGASRG EAYEPLAWNP 450
EEPTGGPHSA PPTAPSPFLF SETTAMKCRS PGCPFTLNVQ HNGFCERCHN 500
ARQLHASHAA DHTRHLDPGK CQACLQDVTR TFNGICSTCF KRTTAEASSS 550
LSTSLPPSCH QRSKSDPSQL VRSPSPHSCH RAGNDAPAGC LSQAARTPGD 600
RTGTSKCRKA GCMYFGTPEN KGFCTLCFIE YRENKHLVAA SGKASPTASR 650
FQNTIPCLGR ECGTLGSTMF EGYCQKCFIE AQNQRFHEAK RTEEQLRSSQ 700
RRDVPRTTQS TSRPKCARAS CKNILACRSE ELCMECQHPN PRMGPGAHRG 750
EPAPEDPPKQ RCWAPACDHF GNAKCNGYCN ECFQFKQMYG 790
Length:790
Mass (Da):89,534
Last modified:July 19, 2005 - v1
Checksum:iEF112EDE0D4F40E9
GO

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AB168334 mRNA. Translation: BAE00458.1.
RefSeqiNP_001270745.1. NM_001283816.1.
UniGeneiMfa.6768.

Genome annotation databases

GeneIDi101867362.
KEGGimcf:101867362.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
AB168334 mRNA. Translation: BAE00458.1 .
RefSeqi NP_001270745.1. NM_001283816.1.
UniGenei Mfa.6768.

3D structure databases

ProteinModelPortali Q4R8W3.
SMRi Q4R8W3. Positions 3-362, 382-419, 597-631, 758-790.
ModBasei Search...
MobiDBi Search...

Protein family/group databases

MEROPSi C64.003.

Protocols and materials databases

Structural Biology Knowledgebase Search...

Genome annotation databases

GeneIDi 101867362.
KEGGi mcf:101867362.

Organism-specific databases

CTDi 7128.

Phylogenomic databases

HOVERGENi HBG059260.
KOi K11859.

Family and domain databases

InterProi IPR003323. OTU.
IPR002653. Znf_A20.
[Graphical view ]
Pfami PF02338. OTU. 1 hit.
PF01754. zf-A20. 6 hits.
[Graphical view ]
SMARTi SM00259. ZnF_A20. 7 hits.
[Graphical view ]
PROSITEi PS50802. OTU. 1 hit.
PS51036. ZF_A20. 7 hits.
[Graphical view ]
ProtoNeti Search...

Publicationsi

  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.

Entry informationi

Entry nameiTNAP3_MACFA
AccessioniPrimary (citable) accession number: Q4R8W3
Entry historyi
Integrated into UniProtKB/Swiss-Prot: January 24, 2006
Last sequence update: July 19, 2005
Last modified: September 3, 2014
This is version 51 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Multifunctional enzyme

Documents

  1. Peptidase families
    Classification of peptidase families and list of entries
  2. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

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