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Q4R8W3

- TNAP3_MACFA

UniProt

Q4R8W3 - TNAP3_MACFA

Protein

Tumor necrosis factor alpha-induced protein 3

Gene

TNFAIP3

Organism
Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at transcript leveli
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    • History
      Entry version 52 (01 Oct 2014)
      Sequence version 1 (19 Jul 2005)
      Previous versions | rss
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    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.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 – 1001By similarity
    Active sitei103 – 1031NucleophileBy similarity
    Active sitei256 – 2561Proton acceptorBy similarity
    Sitei439 – 4402Cleavage; by MALT1By similarity

    Regions

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

    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

    Keywords - Cellular componenti

    Cytoplasm, Lysosome, Nucleus

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy 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-acetylalanineBy similarity
    Modified residuei459 – 4591PhosphoserineBy 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.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.By similarity

    Structurei

    3D structure databases

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

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini92 – 263172OTUPROSITE-ProRule annotationAdd
    BLAST
    Repeati286 – 317321Add
    BLAST
    Repeati324 – 356332Add
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni58 – 300243TRAF-bindingBy similarityAdd
    BLAST
    Regioni157 – 1593Interaction with ubiquitinBy similarity
    Regioni190 – 1923Interaction with ubiquitinBy similarity
    Regioni224 – 2274Interaction with ubiquitinBy similarity
    Regioni286 – 356712 X approximate repeatsAdd
    BLAST
    Regioni369 – 775407Interaction with TNIP1By similarityAdd
    BLAST
    Regioni386 – 45368Interaction with RIPK1By similarityAdd
    BLAST
    Regioni605 – 65551Required for proteosomal degradation of UBE2N and UBE2D3, TRAF6 deubiquitination, and TAX1BP1 interaction with UBE2NBy similarityAdd
    BLAST
    Regioni606 – 790185Sufficient for inhibitory activity of TNF-induced NF-kappa-B activityBy similarityAdd
    BLAST
    Regioni697 – 79094Required for lysosomal localization and for TRAF2 lysosomal degradationBy 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.By similarity
    The OTU domain mediates the deubiquitinase activity.By similarity

    Sequence similaritiesi

    Belongs to the peptidase C64 family.Curated
    Contains 7 A20-type zinc fingers.PROSITE-ProRule annotation
    Contains 1 OTU domain.PROSITE-ProRule annotation

    Zinc finger

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

    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: October 1, 2014
    This is version 52 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