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Protein

TNF receptor-associated factor 3

Gene

Traf3

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

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 MAP3K14.10 Publications

Catalytic activityi

S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N6-ubiquitinyl-[acceptor protein]-L-lysine.

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri67 – 76RING-typePROSITE-ProRule annotation10
Zinc fingeri134 – 189TRAF-type 1PROSITE-ProRule annotationAdd BLAST56
Zinc fingeri190 – 248TRAF-type 2PROSITE-ProRule annotationAdd BLAST59

GO - Molecular functioni

GO - Biological processi

  • apoptotic process Source: UniProtKB-KW
  • innate immune response Source: InterPro
  • negative regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • regulation of apoptotic process Source: InterPro
  • regulation of cytokine production Source: UniProtKB
  • regulation of defense response to virus Source: UniProtKB
  • regulation of interferon-beta production Source: UniProtKB
  • regulation of proteolysis Source: UniProtKB
  • toll-like receptor signaling pathway Source: UniProtKB
  • Toll signaling pathway Source: InterPro
  • tumor necrosis factor-mediated signaling pathway Source: UniProtKB

Keywordsi

Molecular functionTransferase
Biological processApoptosis, Immunity, Ubl conjugation pathway
LigandMetal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-5668541 TNFR2 non-canonical NF-kB pathway
R-MMU-5676594 TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway
R-MMU-5689896 Ovarian tumor domain proteases
R-MMU-936964 Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon

Names & Taxonomyi

Protein namesi
Recommended name:
TNF receptor-associated factor 3 (EC:2.3.2.27)
Alternative name(s):
CD40 receptor-associated factor 1
Short name:
CRAF1
RING-type E3 ubiquitin transferase TRAF3Curated
TRAFAMN
Gene namesi
Name:Traf3
Synonyms:Craf1, Trafamn
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 12

Organism-specific databases

MGIiMGI:108041 Traf3

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cytoplasm, Endosome

Pathology & Biotechi

Disruption phenotypei

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.3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi52C → A: Abolishes inhibition of NFKB2 processing; when associated with A-55. 1 Publication1
Mutagenesisi55C → A: Abolishes inhibition of NFKB2 processing; when associated with A-52. 1 Publication1
Mutagenesisi67C → A: Strongly reduces 'Lys-63'-linked ubiquitination; when associated with A-69. Abolishes inhibition of NFKB2 processing; when associated with A-69. 2 Publications1
Mutagenesisi69H → A: Strongly reduces 'Lys-63'-linked ubiquitination; when associated with A-69. Abolishes inhibition of NFKB2 processing; when associated with A-67. 2 Publications1
Mutagenesisi106K → R: Reduces 'Lys-48'-linked polyubiquitination; when associated with R-155. 1
Mutagenesisi155K → R: Reduces 'Lys-48'-linked polyubiquitination; when associated with R-106. 1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000564021 – 567TNF receptor-associated factor 3Add BLAST567

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki106Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)Curated
Cross-linki155Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)Curated

Post-translational modificationi

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 OTUD5.3 Publications

Keywords - PTMi

Isopeptide bond, Ubl conjugation

Proteomic databases

MaxQBiQ60803
PaxDbiQ60803
PeptideAtlasiQ60803
PRIDEiQ60803

PTM databases

iPTMnetiQ60803
PhosphoSitePlusiQ60803

Expressioni

Tissue specificityi

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.3 Publications

Developmental stagei

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.

Gene expression databases

BgeeiENSMUSG00000021277
CleanExiMM_TRAF3
ExpressionAtlasiQ60803 baseline and differential
GenevisibleiQ60803 MM

Interactioni

Subunit structurei

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). Interacts (via MATH domain) with PTPN22; the interaction promotes TRAF3 polyubiquitination (PubMed:23871208).By similarity1 Publication

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi204304, 26 interactors
DIPiDIP-34050N
IntActiQ60803, 20 interactors
MINTiQ60803
STRINGi10090.ENSMUSP00000021706

Structurei

Secondary structure

1567
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi377 – 409Combined sources33
Beta strandi413 – 421Combined sources9
Helixi424 – 432Combined sources9
Beta strandi444 – 447Combined sources4
Beta strandi452 – 458Combined sources7
Helixi463 – 465Combined sources3
Turni466 – 468Combined sources3
Beta strandi469 – 477Combined sources9
Helixi482 – 484Combined sources3
Beta strandi493 – 497Combined sources5
Beta strandi507 – 511Combined sources5
Helixi518 – 520Combined sources3
Beta strandi524 – 527Combined sources4
Beta strandi531 – 538Combined sources8
Helixi539 – 544Combined sources6
Beta strandi552 – 559Combined sources8

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4GHUX-ray2.20A376-567[»]
ProteinModelPortaliQ60803
SMRiQ60803
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini414 – 559MATHPROSITE-ProRule annotationAdd BLAST146

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili266 – 337Sequence analysisAdd BLAST72

Domaini

The MATH/TRAF domain binds to receptor cytoplasmic domains.1 Publication
The Ring-type zinc finger domain is required for its function in down-regulation of NFKB2 proteolytic processing.1 Publication

Sequence similaritiesi

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri67 – 76RING-typePROSITE-ProRule annotation10
Zinc fingeri134 – 189TRAF-type 1PROSITE-ProRule annotationAdd BLAST56
Zinc fingeri190 – 248TRAF-type 2PROSITE-ProRule annotationAdd BLAST59

Keywords - Domaini

Coiled coil, Repeat, Zinc-finger

Phylogenomic databases

eggNOGiENOG410ISDV Eukaryota
ENOG410YQ97 LUCA
GeneTreeiENSGT00550000074359
HOGENOMiHOG000231557
HOVERGENiHBG058222
InParanoidiQ60803
KOiK03174
OMAiFCETCMA
OrthoDBiEOG091G0GHD
TreeFamiTF321154

Family and domain databases

CDDicd03777 MATH_TRAF3, 1 hit
Gene3Di2.60.210.10, 1 hit
3.30.40.10, 2 hits
InterProiView protein in InterPro
IPR002083 MATH/TRAF_dom
IPR012227 TNF_rcpt--assoc_TRAF
IPR008974 TRAF-like
IPR027128 TRAF3
IPR037304 TRAF3_MATH
IPR001841 Znf_RING
IPR013083 Znf_RING/FYVE/PHD
IPR017907 Znf_RING_CS
IPR001293 Znf_TRAF
PANTHERiPTHR10131:SF76 PTHR10131:SF76, 1 hit
PfamiView protein in Pfam
PF02176 zf-TRAF, 1 hit
PIRSFiPIRSF015614 TRAF, 1 hit
SMARTiView protein in SMART
SM00061 MATH, 1 hit
SUPFAMiSSF49599 SSF49599, 3 hits
PROSITEiView protein in PROSITE
PS50144 MATH, 1 hit
PS00518 ZF_RING_1, 1 hit
PS50089 ZF_RING_2, 1 hit
PS50145 ZF_TRAF, 2 hits

Sequencei

Sequence statusi: Complete.

Q60803-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MESSKKMDAA GTLQPNPPLK LQPDRGAGSV LVPEQGGYKE KFVKTVEDKY
60 70 80 90 100
KCEKCRLVLC NPKQTECGHR FCESCMAALL SSSSPKCTAC QESIIKDKVF
110 120 130 140 150
KDNCCKREIL ALQVYCRNEG RGCAEQLTLG HLLVHLKNEC QFEELPCLRA
160 170 180 190 200
DCKEKVLRKD LRDHVEKACK YREATCSHCK SQVPMIKLQK HEDTDCPCVV
210 220 230 240 250
VSCPHKCSVQ TLLRSELSAH LSECVNAPST CSFKRYGCVF QGTNQQIKAH
260 270 280 290 300
EASSAVQHVN LLKEWSNSLE KKVSLLQNES VEKNKSIQSL HNQICSFEIE
310 320 330 340 350
IERQKEMLRN NESKILHLQR VIDSQAEKLK ELDKEIRPFR QNWEEADSMK
360 370 380 390 400
SSVESLQNRV TELESVDKSA GQAARNTGLL ESQLSRHDQM LSVHDIRLAD
410 420 430 440 450
MDLRFQVLET ASYNGVLIWK IRDYKRRKQE AVMGKTLSLY SQPFYTGYFG
460 470 480 490 500
YKMCARVYLN GDGMGKGTHL SLFFVIMRGE YDALLPWPFK QKVTLMLMDQ
510 520 530 540 550
GSSRRHLGDA FKPDPNSSSF KKPTGEMNIA SGCPVFVAQT VLENGTYIKD
560
DTIFIKVIVD TSDLPDP
Length:567
Mass (Da):64,294
Last modified:July 27, 2011 - v2
Checksum:iEC282EFFF84E5A3F
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti72 – 73CE → WQ in AAC52710 (PubMed:8660894).Curated2
Sequence conflicti390M → T in AAC52175 (PubMed:7533327).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
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
CCDSiCCDS26175.1
PIRiI49272
RefSeqiNP_035762.2, NM_011632.3
XP_006515861.1, XM_006515798.2
XP_006515862.1, XM_006515799.1
XP_006515863.1, XM_006515800.2
XP_006515864.1, XM_006515801.2
UniGeneiMm.27431

Genome annotation databases

EnsembliENSMUST00000021706; ENSMUSP00000021706; ENSMUSG00000021277
GeneIDi22031
KEGGimmu:22031
UCSCiuc007pcl.2 mouse

Similar proteinsi

Entry informationi

Entry nameiTRAF3_MOUSE
AccessioniPrimary (citable) accession number: Q60803
Secondary accession number(s): B2RPW3, Q62380
Entry historyiIntegrated into UniProtKB/Swiss-Prot: May 30, 2000
Last sequence update: July 27, 2011
Last modified: March 28, 2018
This is version 171 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome
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Main funding by: National Institutes of Health