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Q60803 (TRAF3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 134. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
TNF receptor-associated factor 3

EC=6.3.2.-
Alternative name(s):
CD40 receptor-associated factor 1
Short name=CRAF1
TRAFAMN
Gene names
Name:Traf3
Synonyms:Craf1, Trafamn
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length567 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Regulates pathways leading to the activation of NF-kappa-B and MAP kinases, and plays a central role in the regulation of B-cell survival. Part of signaling pathways leading to the production of cytokines and interferon. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Plays a role in the regulation of antiviral responses. Is an essential constituent of several E3 ubiquitin-protein ligase complexes. May have E3 ubiquitin-protein ligase activity and promote 'Lys-63'-linked ubiquitination of target proteins. Inhibits activation of NF-kappa-B in response to LTBR stimulation. Inhibits TRAF2-mediated activation of NF-kappa-B. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.12 Ref.13 Ref.14 Ref.15

Subunit structure

Homotrimer. Heterotrimer with TRAF2 and TRAF5. Interacts with LTBR/TNFRSF3, TNFRSF4, TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF13C TNFRSF17/BCMA, TLR4 and EDAR. Interacts with MAP3K5, MAP3K14, TRAIP/TRIP, TDP2/TTRAP, TANK/ITRAF and TRAF3IP1. Interaction with TNFRSF5/CD40 is modulated by TANK/ITRAF, which competes for the same binding site. Interacts with TICAM1. Interacts with TRAFD1. Interacts with OTUB1, OTUB2 and OTUD5. Interacts with RNF216, MAVS, OPTN and TBK1 By similarity. Identified in a complex with TRAF2, MAP3K14 and BIRC3. Upon exposure to bacterial lipopolysaccharide (LPS), recruited to a transient complex containing TLR4, TRAF3, TRAF6, IKBKG, MAP3K7, MYD88, TICAM1, BIRC2, BIRC3 and UBE2N. Interacts (via RING-type zinc finger domain) with SRC. Interacts with CARD14 By similarity. Ref.1 Ref.7 Ref.8 Ref.9 Ref.11 Ref.12 Ref.13 Ref.15

Subcellular location

Cytoplasm. Endosome. Note: Undergoes endocytosis together with TLR4 upon LPS signaling. Ref.15

Tissue specificity

Detected in bone marrow macrophages and spleen B-cells (at protein level). In adult, highest in brain. Also found in kidney, heart, thymus, spleen, lung, muscle, testis and ovary. Not found in liver. Ref.2 Ref.12 Ref.15

Developmental stage

In the embryo, expressed from E6.5 with highest levels found between E11.5 and E13.5. At late stages of gestation, from E14.5, only low levels are detected.

Domain

The MATH/TRAF domain binds to receptor cytoplasmic domains. Ref.9

The Ring-type zinc finger domain is required for its function in down-regulation of NFKB2 proteolytic processing. Ref.9

Post-translational modification

Undergoes 'Lys-48'-linked polyubiquitination, leading to its proteasomal degradation in response to signaling by TNFSF13B, TLR4 or through CD40. 'Lys-48'-linked polyubiquitinated form is deubiquitinated by OTUD7B, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B. Undergoes 'Lys-63'-linked ubiquitination during early stages of virus infection, and 'Lys-48'-linked ubiquitination during later stages. Undergoes both 'Lys-48'-linked and 'Lys-63'-linked ubiquitination in response to TLR3 and TLR4 signaling. Deubiquitinated by OTUB1, OTUB2 and OTUD5.

Disruption phenotype

Newborns appear normal, but do not thrive. Their blood glucose levels and leukocyte levels decrease steadily, the spleen size is dramatically reduced, and they become progressively runted. They die about ten days after birth. Mice exhibit abnormally high MAP3K14 protein levels and constitutive proteolytic processing of NFKB2/p100, leading to constitutive activation of NF-kappa-B. Ref.5 Ref.6 Ref.12

Sequence similarities

Belongs to the TNF receptor-associated factor family. A subfamily.

Contains 1 MATH domain.

Contains 1 RING-type zinc finger.

Contains 2 TRAF-type zinc fingers.

Ontologies

Keywords
   Biological processApoptosis
Immunity
Ubl conjugation pathway
   Cellular componentCytoplasm
Endosome
   DomainCoiled coil
Repeat
Zinc-finger
   LigandMetal-binding
Zinc
   Molecular functionLigase
   PTMIsopeptide bond
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processToll signaling pathway

Inferred from electronic annotation. Source: InterPro

apoptotic process

Inferred from electronic annotation. Source: UniProtKB-KW

innate immune response

Inferred from electronic annotation. Source: InterPro

negative regulation of NF-kappaB transcription factor activity

Inferred from mutant phenotype Ref.6. Source: UniProtKB

regulation of apoptotic process

Inferred from electronic annotation. Source: InterPro

regulation of cytokine production

Inferred from mutant phenotype Ref.7. Source: UniProtKB

regulation of defense response to virus

Inferred from mutant phenotype Ref.7. Source: UniProtKB

regulation of interferon-beta production

Inferred from mutant phenotype Ref.7. Source: UniProtKB

regulation of proteolysis

Inferred from direct assay Ref.9. Source: UniProtKB

toll-like receptor signaling pathway

Inferred from mutant phenotype Ref.7. Source: UniProtKB

tumor necrosis factor-mediated signaling pathway

Inferred from mutant phenotype Ref.6. Source: UniProtKB

   Cellular_componentCD40 receptor complex

Inferred from direct assay PubMed 20614026. Source: BHF-UCL

cytoplasmic side of plasma membrane

Inferred from direct assay PubMed 20614026. Source: BHF-UCL

endosome

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionprotein kinase binding

Inferred from physical interaction Ref.9. Source: UniProtKB

ubiquitin-protein ligase activity

Inferred from electronic annotation. Source: InterPro

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Binary interactions

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 567567TNF receptor-associated factor 3
PRO_0000056402

Regions

Domain414 – 559146MATH
Zinc finger67 – 7610RING-type
Zinc finger134 – 18956TRAF-type 1
Zinc finger190 – 24859TRAF-type 2
Coiled coil266 – 33772 Potential

Amino acid modifications

Cross-link106Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Probable
Cross-link155Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) Probable

Experimental info

Mutagenesis521C → A: Abolishes inhibition of NFKB2 processing; when associated with A-55. Ref.9
Mutagenesis551C → A: Abolishes inhibition of NFKB2 processing; when associated with A-52. Ref.9
Mutagenesis671C → A: Strongly reduces 'Lys-63'-linked ubiquitination; when associated with A-69. Abolishes inhibition of NFKB2 processing; when associated with A-69. Ref.9 Ref.15
Mutagenesis691H → A: Strongly reduces 'Lys-63'-linked ubiquitination; when associated with A-69. Abolishes inhibition of NFKB2 processing; when associated with A-67. Ref.9 Ref.15
Mutagenesis1061K → R: Reduces 'Lys-48'-linked polyubiquitination; when associated with R-155.
Mutagenesis1551K → R: Reduces 'Lys-48'-linked polyubiquitination; when associated with R-106.
Sequence conflict72 – 732CE → WQ in AAC52710. Ref.2
Sequence conflict3901M → T in AAC52175. Ref.1

Secondary structure

.............................. 567
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Q60803 [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: EC282EFFF84E5A3F

FASTA56764,294
        10         20         30         40         50         60 
MESSKKMDAA GTLQPNPPLK LQPDRGAGSV LVPEQGGYKE KFVKTVEDKY KCEKCRLVLC 

        70         80         90        100        110        120 
NPKQTECGHR FCESCMAALL SSSSPKCTAC QESIIKDKVF KDNCCKREIL ALQVYCRNEG 

       130        140        150        160        170        180 
RGCAEQLTLG HLLVHLKNEC QFEELPCLRA DCKEKVLRKD LRDHVEKACK YREATCSHCK 

       190        200        210        220        230        240 
SQVPMIKLQK HEDTDCPCVV VSCPHKCSVQ TLLRSELSAH LSECVNAPST CSFKRYGCVF 

       250        260        270        280        290        300 
QGTNQQIKAH EASSAVQHVN LLKEWSNSLE KKVSLLQNES VEKNKSIQSL HNQICSFEIE 

       310        320        330        340        350        360 
IERQKEMLRN NESKILHLQR VIDSQAEKLK ELDKEIRPFR QNWEEADSMK SSVESLQNRV 

       370        380        390        400        410        420 
TELESVDKSA GQAARNTGLL ESQLSRHDQM LSVHDIRLAD MDLRFQVLET ASYNGVLIWK 

       430        440        450        460        470        480 
IRDYKRRKQE AVMGKTLSLY SQPFYTGYFG YKMCARVYLN GDGMGKGTHL SLFFVIMRGE 

       490        500        510        520        530        540 
YDALLPWPFK QKVTLMLMDQ GSSRRHLGDA FKPDPNSSSF KKPTGEMNIA SGCPVFVAQT 

       550        560 
VLENGTYIKD DTIFIKVIVD TSDLPDP 

« Hide

References

« Hide 'large scale' references
[1]"Involvement of CRAF1, a relative of TRAF, in CD40 signaling."
Cheng G., Cleary A.M., Ye Z.S., Hong D.I., Lederman S., Baltimore D.
Science 267:1494-1498(1995) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH TNFRSF5.
[2]"A candidate gene for the amnionless gastrulation stage mouse mutation encodes a TRAF-related protein."
Wang X., Bornslaeger E.A., Haub O., Tomihara-Newberger C., Lonberg N., Dinulos M.B., Disteche C.M., Copeland N.G., Gilbert D.J., Jenkins N.A., Lacy E.
Dev. Biol. 177:274-290(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY.
Strain: C57BL/6J.
Tissue: Brain.
[3]Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.
Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"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].
Tissue: Brain.
[5]"Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses."
Xu Y., Cheng G., Baltimore D.
Immunity 5:407-415(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[6]"Rescue of TRAF3-null mice by p100 NF-kappa B deficiency."
He J.Q., Zarnegar B., Oganesyan G., Saha S.K., Yamazaki S., Doyle S.E., Dempsey P.W., Cheng G.
J. Exp. Med. 203:2413-2418(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION.
[7]"Specificity in Toll-like receptor signalling through distinct effector functions of TRAF3 and TRAF6."
Hacker H., Redecke V., Blagoev B., Kratchmarova I., Hsu L.C., Wang G.G., Kamps M.P., Raz E., Wagner H., Hacker G., Mann M., Karin M.
Nature 439:204-207(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MYD88, IDENTIFICATION IN A COMPLEX WITH TRAF6.
[8]"Critical role of TRAF3 in the Toll-like receptor-dependent and -independent antiviral response."
Oganesyan G., Saha S.K., Guo B., He J.Q., Shahangian A., Zarnegar B., Perry A., Cheng G.
Nature 439:208-211(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TICAM1, FUNCTION.
[9]"Specificity of TRAF3 in its negative regulation of the noncanonical NF-kappa B pathway."
He J.Q., Saha S.K., Kang J.R., Zarnegar B., Cheng G.
J. Biol. Chem. 282:3688-3694(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DOMAIN, INTERACTION WITH MAP3K14, MUTAGENESIS OF CYS-52; CYS-55; CYS-67 AND HIS-69.
[10]"TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signals delivered to B cells by the BAFF receptor."
Gardam S., Sierro F., Basten A., Mackay F., Brink R.
Immunity 28:391-401(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[11]"FLN29 deficiency reveals its negative regulatory role in the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like helicase signaling pathway."
Sanada T., Takaesu G., Mashima R., Yoshida R., Kobayashi T., Yoshimura A.
J. Biol. Chem. 283:33858-33864(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH TRAFD1.
[12]"Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling."
Vallabhapurapu S., Matsuzawa A., Zhang W., Tseng P.H., Keats J.J., Wang H., Vignali D.A., Bergsagel P.L., Karin M.
Nat. Immunol. 9:1364-1370(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, DISRUPTION PHENOTYPE, IDENTIFICATION IN A COMPLEX WITH TRAF2; BIRC3 AND MAP3K14, UBIQUITINATION, TISSUE SPECIFICITY.
[13]"Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK."
Zarnegar B.J., Wang Y., Mahoney D.J., Dempsey P.W., Cheung H.H., He J., Shiba T., Yang X., Yeh W.C., Mak T.W., Korneluk R.G., Cheng G.
Nat. Immunol. 9:1371-1378(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH MAP3K14.
[14]"TRAF2 and TRAF3 independently mediate Ig class switching driven by CD40."
Jabara H.H., Weng Y., Sannikova T., Geha R.S.
Int. Immunol. 21:477-488(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[15]"Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines."
Tseng P.H., Matsuzawa A., Zhang W., Mino T., Vignali D.A., Karin M.
Nat. Immunol. 11:70-75(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, E3 PROTEIN-UBIQUITIN LIGASE ACTIVITY, MUTAGENESIS OF CYS-67 AND HIS-69, SUBCELLULAR LOCATION, SUBUNIT, INTERACTION WITH TLR4, IDENTIFICATION IN A COMPLEX WITH TLR4; TRAF6; MAP3K7; MYD88; IKBKG; TICAM1; BIRC2; BIRC3 AND UBE2N, UBIQUITINATION, TISSUE SPECIFICITY.
[16]"OTUD7B controls non-canonical NF-kappaB activation through deubiquitination of TRAF3."
Hu H., Brittain G.C., Chang J.H., Puebla-Osorio N., Jin J., Zal A., Xiao Y., Cheng X., Chang M., Fu Y.X., Zal T., Zhu C., Sun S.C.
Nature 494:371-374(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, DEUBIQUITINATION BY OTUD7B.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U21050 mRNA. Translation: AAC52175.1.
U33840 mRNA. Translation: AAC52710.1.
CH466549 Genomic DNA. Translation: EDL18642.1.
BC137634 mRNA. Translation: AAI37635.1.
BC137635 mRNA. Translation: AAI37636.1.
PIRI49272.
RefSeqNP_035762.2. NM_011632.3.
XP_006515861.1. XM_006515798.1.
XP_006515862.1. XM_006515799.1.
XP_006515863.1. XM_006515800.1.
XP_006515864.1. XM_006515801.1.
UniGeneMm.27431.

3D structure databases

PDBe
RCSB PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
4GHUX-ray2.20A376-567[»]
ProteinModelPortalQ60803.
SMRQ60803. Positions 37-257, 376-567.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid204304. 16 interactions.
DIPDIP-34050N.
IntActQ60803. 7 interactions.
MINTMINT-1506326.

PTM databases

PhosphoSiteQ60803.

Proteomic databases

PaxDbQ60803.
PRIDEQ60803.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000021706; ENSMUSP00000021706; ENSMUSG00000021277.
GeneID22031.
KEGGmmu:22031.
UCSCuc007pcl.1. mouse.

Organism-specific databases

CTD7187.
MGIMGI:108041. Traf3.

Phylogenomic databases

eggNOGNOG239194.
GeneTreeENSGT00550000074359.
HOGENOMHOG000231557.
HOVERGENHBG058222.
InParanoidB2RPW3.
KOK03174.
OMAYGCTFQG.
OrthoDBEOG7966G5.
TreeFamTF321154.

Gene expression databases

ArrayExpressQ60803.
BgeeQ60803.
CleanExMM_TRAF3.
GenevestigatorQ60803.

Family and domain databases

Gene3D3.30.40.10. 1 hit.
3.90.890.10. 1 hit.
InterProIPR002083. MATH.
IPR013323. SIAH-type.
IPR012227. TNF_rcpt--assoc_TRAF.
IPR008974. TRAF-like.
IPR027128. TRAF3.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
IPR001293. Znf_TRAF.
[Graphical view]
PANTHERPTHR10131:SF45. PTHR10131:SF45. 1 hit.
PfamPF00917. MATH. 1 hit.
[Graphical view]
PIRSFPIRSF015614. TRAF. 1 hit.
SMARTSM00061. MATH. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]
SUPFAMSSF49599. SSF49599. 3 hits.
PROSITEPS50144. MATH. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
PS50145. ZF_TRAF. 2 hits.
[Graphical view]
ProtoNetSearch...

Other

NextBio301784.
PROQ60803.
SOURCESearch...

Entry information

Entry nameTRAF3_MOUSE
AccessionPrimary (citable) accession number: Q60803
Secondary accession number(s): B2RPW3, Q62380
Entry history
Integrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: July 27, 2011
Last modified: April 16, 2014
This is version 134 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot