ID TRAF6_BOVIN Reviewed; 542 AA.
AC Q3ZCC3;
DT 09-FEB-2010, integrated into UniProtKB/Swiss-Prot.
DT 27-SEP-2005, sequence version 1.
DT 27-MAR-2024, entry version 160.
DE RecName: Full=TNF receptor-associated factor 6;
DE EC=2.3.2.27;
DE AltName: Full=E3 ubiquitin-protein ligase TRAF6;
DE AltName: Full=RING-type E3 ubiquitin transferase TRAF6 {ECO:0000305};
GN Name=TRAF6;
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Mammary gland;
RX PubMed=16621030; DOI=10.1016/j.vetimm.2006.03.003;
RA Connor E.E., Cates E.A., Williams J.L., Bannerman D.D.;
RT "Cloning and radiation hybrid mapping of bovine toll-like receptor-4 (TLR-
RT 4) signaling molecules.";
RL Vet. Immunol. Immunopathol. 112:302-308(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RA Werling D., Willcocks S.;
RT "Identification of signalling molecules involved in bovine TLR
RT signalling.";
RL Submitted (FEB-2006) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=Crossbred X Angus; TISSUE=Ileum;
RG NIH - Mammalian Gene Collection (MGC) project;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: E3 ubiquitin ligase that, together with UBE2N and UBE2V1,
CC mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains
CC conjugated to proteins, such as ECSIT, IKBKG, IRAK1, AKT1 and AKT2.
CC Also mediates ubiquitination of free/unanchored polyubiquitin chain
CC that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B
CC and JUN (By similarity). Seems to also play a role in dendritic cells
CC (DCs) maturation and/or activation (By similarity). Represses c-Myb-
CC mediated transactivation, in B-lymphocytes. Adapter protein that seems
CC to play a role in signal transduction initiated via TNF receptor, IL-1
CC receptor and IL-17 receptor (By similarity). Regulates osteoclast
CC differentiation by mediating the activation of adapter protein complex
CC 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together
CC with MAP3K8, mediates CD40 signals that activate ERK in B-cells and
CC macrophages, and thus may play a role in the regulation of
CC immunoglobulin production (By similarity). Participates also in the TCR
CC signaling by ubiquitinating LAT (By similarity).
CC {ECO:0000250|UniProtKB:P70196, ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27;
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Homotrimer. Homooligomer. N-terminal region is dimeric while
CC C-terminal region is trimeric; maybe providing a mode of
CC oligomerization. Upon IL1B treatment, forms a complex with PELI1,
CC IRAK1, IRAK4 and MYD88; this complex recruits MAP3K7/TAK1, TAB1 and
CC TAB2 to mediate NF-kappa-B activation. Direct binding of SMAD6 to PELI1
CC prevents the complex formation and hence negatively regulates IL1R-TLR
CC signaling and eventually NF-kappa-B-mediated gene expression. Binds to
CC TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK2,
CC IRAK3, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting
CC protein TRIP and TNF receptor associated protein TDP2. Interacts with
CC IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary
CC complex with SQSTM1 and PRKCZ (By similarity). Interacts with PELI2 and
CC PELI3. Binds UBE2V1. Interacts with TAX1BP1; this interaction mediates
CC deubiquitination of TRAF6 and inhibition of NF-kappa-B activation (By
CC similarity). Interacts with ZNF675. Interacts with ARRB1 and ARRB2.
CC Interacts with MAP3K7 and TAB1/MAP3K7IP1; during IL-1 signaling.
CC Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1.
CC Interacts with AKT1, AKT2 and AKT3. Interacts (via TRAF domains) with
CC NUMBL (via C-terminal). Interacts with RBCK1. Interacts with LIMD1 (via
CC LIM domains) (By similarity). Interacts with RSAD2/viperin (By
CC similarity). Interacts (via C-terminus) with EIF2AK2/PKR (via the
CC kinase catalytic domain) (By similarity). Interacts with ZFAND5.
CC Interacts with IL1RL1. Interacts with TRAFD1. Interacts with AJUBA.
CC Interacts with MAVS/IPS1. Interacts (via TRAF domains) with DYNC2I2
CC (via WD domains). Interacts with IFIT3 (via N-terminus). Interacts with
CC TICAM2. Interacts with CARD14. Interacts with CD40 and MAP3K8; the
CC interaction is required for ERK activation (By similarity). Interacts
CC with TICAM1 and this interaction is enhanced in the presence of WDFY1.
CC Interacts with TANK; this interaction increases in response to DNA
CC damage. Interacts with USP10; this interaction increases in response to
CC DNA damage. Interacts with ZC3H12A; this interaction increases in
CC response to DNA damage and is stimulated by TANK (By similarity).
CC Interacts with WDFY3 (By similarity). Interacts with TRIM13 (By
CC similarity). Interacts with GPS2 (By similarity). Interacts (via C-
CC terminus) with SASH1. Interacts with LRRC19. Interacts with IL17RA and
CC TRAF3IP2. Interacts with TOMM70. Interacts with AMBRA1; interaction is
CC required to mediate 'Lys-63'-linked ubiquitination of ULK1 (By
CC similarity). Interacts with CRBN; this interaction inhibits TLR4-
CC mediated signaling by preventing TRAF6-mediated ubiquitination of ECSIT
CC (By similarity). {ECO:0000250|UniProtKB:P70196,
CC ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9Y4K3}.
CC Cytoplasm, cell cortex {ECO:0000250|UniProtKB:Q9Y4K3}. Nucleus
CC {ECO:0000250|UniProtKB:Q9Y4K3}. Lipid droplet
CC {ECO:0000250|UniProtKB:P70196}. Note=RSAD2/viperin recruits it to the
CC lipid droplet. {ECO:0000250|UniProtKB:P70196}.
CC -!- DOMAIN: The coiled coil domain mediates homo- and hetero-
CC oligomerization. {ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- DOMAIN: The MATH/TRAF domain binds to receptor cytoplasmic domains.
CC {ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- PTM: Sumoylated on Lys-125, Lys-143 and Lys-473 with SUMO1.
CC {ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- PTM: Polyubiquitinated on Lys-125 by TRAF3IP2; after cell stimulation
CC with IL17A (By similarity). Polyubiquitinated on Lys-125; after cell
CC stimulation with IL1B or TGFB. This ligand-induced cell stimulation
CC leads to dimerization/oligomerization of TRAF6 molecules, followed by
CC auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6
CC activation. This 'Lys-63' site-specific poly-ubiquitination appears to
CC be associated with the activation of signaling molecules. Endogenous
CC autoubiquitination occurs only for the cytoplasmic form.
CC Deubiquitinated by USP10 in a TANK-dependent manner, leading to the
CC negative regulation of NF-kappa-B signaling upon DNA damage. LRRC19
CC induces 'Lys-63' ubiquitination (By similarity). Ubiquitinated at Lys-
CC 339 by the SCF(FBXL2) complex, leading to its degradation by the
CC proteasome (By similarity). {ECO:0000250|UniProtKB:P70196,
CC ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- SIMILARITY: Belongs to the TNF receptor-associated factor family. A
CC subfamily. {ECO:0000305}.
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DR EMBL; DQ319074; ABC47877.1; -; mRNA.
DR EMBL; DQ407276; ABD72516.1; -; mRNA.
DR EMBL; BC102522; AAI02523.1; -; mRNA.
DR RefSeq; NP_001029833.1; NM_001034661.2.
DR RefSeq; XP_005216441.1; XM_005216384.3.
DR RefSeq; XP_005216442.1; XM_005216385.3.
DR AlphaFoldDB; Q3ZCC3; -.
DR BMRB; Q3ZCC3; -.
DR SMR; Q3ZCC3; -.
DR STRING; 9913.ENSBTAP00000021630; -.
DR PaxDb; 9913-ENSBTAP00000021630; -.
DR Ensembl; ENSBTAT00000021630.5; ENSBTAP00000021630.4; ENSBTAG00000036009.3.
DR GeneID; 539124; -.
DR KEGG; bta:539124; -.
DR CTD; 7189; -.
DR VEuPathDB; HostDB:ENSBTAG00000036009; -.
DR VGNC; VGNC:36278; TRAF6.
DR eggNOG; KOG0297; Eukaryota.
DR GeneTree; ENSGT00940000155426; -.
DR HOGENOM; CLU_021061_5_0_1; -.
DR InParanoid; Q3ZCC3; -.
DR OMA; FMHLQAL; -.
DR OrthoDB; 2913784at2759; -.
DR TreeFam; TF321154; -.
DR Reactome; R-BTA-1257604; PIP3 activates AKT signaling.
DR Reactome; R-BTA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR Reactome; R-BTA-193692; Regulated proteolysis of p75NTR.
DR Reactome; R-BTA-202424; Downstream TCR signaling.
DR Reactome; R-BTA-205043; NRIF signals cell death from the nucleus.
DR Reactome; R-BTA-209543; p75NTR recruits signalling complexes.
DR Reactome; R-BTA-209560; NF-kB is activated and signals survival.
DR Reactome; R-BTA-2871837; FCERI mediated NF-kB activation.
DR Reactome; R-BTA-450302; activated TAK1 mediates p38 MAPK activation.
DR Reactome; R-BTA-450321; JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1.
DR Reactome; R-BTA-5607764; CLEC7A (Dectin-1) signaling.
DR Reactome; R-BTA-5689880; Ub-specific processing proteases.
DR Reactome; R-BTA-5689896; Ovarian tumor domain proteases.
DR Reactome; R-BTA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
DR Reactome; R-BTA-9020702; Interleukin-1 signaling.
DR Reactome; R-BTA-937039; IRAK1 recruits IKK complex.
DR Reactome; R-BTA-937042; IRAK2 mediated activation of TAK1 complex.
DR Reactome; R-BTA-937072; TRAF6-mediated induction of TAK1 complex within TLR4 complex.
DR Reactome; R-BTA-9645460; Alpha-protein kinase 1 signaling pathway.
DR Reactome; R-BTA-975138; TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation.
DR Reactome; R-BTA-975144; IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation.
DR Reactome; R-BTA-975163; IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation.
DR Reactome; R-BTA-9758274; Regulation of NF-kappa B signaling.
DR Reactome; R-BTA-975871; MyD88 cascade initiated on plasma membrane.
DR UniPathway; UPA00143; -.
DR Proteomes; UP000009136; Chromosome 15.
DR Bgee; ENSBTAG00000036009; Expressed in oocyte and 104 other cell types or tissues.
DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
DR GO; GO:0005811; C:lipid droplet; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:InterPro.
DR GO; GO:0032813; F:tumor necrosis factor receptor superfamily binding; IBA:GO_Central.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IBA:GO_Central.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IBA:GO_Central.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006974; P:DNA damage response; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; IBA:GO_Central.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:UniProt.
DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IBA:GO_Central.
DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; ISS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0070534; P:protein K63-linked ubiquitination; ISS:UniProtKB.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:InterPro.
DR GO; GO:0043122; P:regulation of canonical NF-kappaB signal transduction; IBA:GO_Central.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IBA:GO_Central.
DR CDD; cd03776; MATH_TRAF6; 1.
DR CDD; cd16643; mRING-HC-C3HC3D_TRAF6; 1.
DR Gene3D; 3.30.40.10; Zinc/RING finger domain, C3HC4 (zinc finger); 3.
DR InterPro; IPR002083; MATH/TRAF_dom.
DR InterPro; IPR012227; TNF_rcpt-assoc_TRAF_met.
DR InterPro; IPR008974; TRAF-like.
DR InterPro; IPR037309; TRAF6_MATH.
DR InterPro; IPR027139; TRAF6_RING-HC.
DR InterPro; IPR041310; TRAF6_Z2.
DR InterPro; IPR049342; TRAF_MEP1_MATH_dom.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR InterPro; IPR001293; Znf_TRAF.
DR PANTHER; PTHR10131; TNF RECEPTOR ASSOCIATED FACTOR; 1.
DR PANTHER; PTHR10131:SF94; TNF RECEPTOR-ASSOCIATED FACTOR 6; 1.
DR Pfam; PF21355; TRAF-mep_MATH; 1.
DR Pfam; PF18048; TRAF6_Z2; 1.
DR Pfam; PF13923; zf-C3HC4_2; 1.
DR Pfam; PF02176; zf-TRAF; 1.
DR PIRSF; PIRSF015614; TRAF; 1.
DR SMART; SM00061; MATH; 1.
DR SMART; SM00184; RING; 1.
DR SUPFAM; SSF57850; RING/U-box; 1.
DR SUPFAM; SSF49599; TRAF domain-like; 3.
DR PROSITE; PS50144; MATH; 1.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
DR PROSITE; PS50145; ZF_TRAF; 2.
PE 2: Evidence at transcript level;
KW Coiled coil; Cytoplasm; DNA damage; Immunity; Isopeptide bond;
KW Lipid droplet; Metal-binding; Nucleus; Osteopetrosis; Reference proteome;
KW Repeat; Transferase; Ubl conjugation; Ubl conjugation pathway; Zinc;
KW Zinc-finger.
FT CHAIN 1..542
FT /note="TNF receptor-associated factor 6"
FT /id="PRO_0000391607"
FT DOMAIN 370..519
FT /note="MATH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00129"
FT ZN_FING 71..110
FT /note="RING-type; degenerate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 151..203
FT /note="TRAF-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT ZN_FING 204..260
FT /note="TRAF-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT REGION 1..374
FT /note="Interaction with TAX1BP1"
FT /evidence="ECO:0000250"
FT REGION 375..542
FT /note="Interaction with TANK"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3"
FT COILED 310..368
FT /evidence="ECO:0000255"
FT CROSSLNK 125
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250"
FT CROSSLNK 125
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3"
FT CROSSLNK 143
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT CROSSLNK 339
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:P70196"
FT CROSSLNK 473
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
SQ SEQUENCE 542 AA; 61647 MW; 697EC4641DDDAD76 CRC64;
MSLLHCENSC GSSQSESDCC AAMAASSCGT AAKDDSVSGT ASTVTLSSSF MEEIQGYDVE
FDPPLESKYE CPICLMALRE AVQTPCGHRF CKACIIKSIR DAGHKCPVDN EILLENQLFP
DNFAKREILS LMVKCPNEGC LHKMELRHLE EHQAHCEFAL MSCPQCQRPF QKCHLNIHIL
KECPRRQVPC ENCAVSMAFE DKEIHEQNCP LANVICEYCN TMLIREQMPN HYDLDCPTAP
VPCTFSAFGC HEKMQRNHLA RHLQENTQSH MRMMAQAVQT LSLAVAPVPQ CTMPLYDSVP
PTRPSSGRHS EVHNFQETIQ QLEGRLVRQD HQIRELTAKM ETQSMYVNEL KRTIRTLEDK
VAEIEAQQCN GIYIWKIGNF GMHLKSQEEE KPVVIHSPGF YTGKPGYKLC MRLHLQLPSA
QRCANYISLF VHTMQGEYDS HLPWPFQGTI RLTILDQSEA AVRQNHEEIM DAKPELLAFQ
RPTIPRNPKG FGYVTFMHLE ALRQRTFIKD DTLLVRCEVS TRFDMGSLRR EGFQPRSTDS
GI
//
