TRAF6_CERAT
ID TRAF6_CERAT Reviewed; 522 AA.
AC B6CJY4;
DT 09-FEB-2010, integrated into UniProtKB/Swiss-Prot.
DT 25-NOV-2008, sequence version 1.
DT 03-AUG-2022, entry version 87.
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 Cercocebus atys (Sooty mangabey) (Cercocebus torquatus atys).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC Cercopithecidae; Cercopithecinae; Cercocebus.
OX NCBI_TaxID=9531;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=18806803; DOI=10.1038/nm.1871;
RA Mandl J.N., Barry A.P., Vanderford T.H., Kozyr N., Chavan R., Klucking S.,
RA Barrat F.J., Coffman R.L., Staprans S.I., Feinberg M.B.;
RT "Divergent TLR7 and TLR9 signaling and type I interferon production
RT distinguish pathogenic and nonpathogenic AIDS virus infections.";
RL Nat. Med. 14:1077-1087(2008).
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 IKBKG, IRAK1, AKT1 and AKT2. Also
CC mediates ubiquitination of free/unanchored polyubiquitin chain that
CC leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and
CC JUN (By similarity). Seems to also play a role in dendritic cells (DCs)
CC maturation and/or activation (By similarity). Represses c-Myb-mediated
CC transactivation, in B-lymphocytes. Adapter protein that seems to play a
CC role in signal transduction initiated via TNF receptor, IL-1 receptor
CC 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).
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. Interacts with ZNF675.
CC Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and
CC TAB1/MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts
CC with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3.
CC Interacts (via TRAF domains) with NUMBL (via C-terminal). Interacts
CC with RBCK1. Interacts with LIMD1 (via LIM domains) (By similarity).
CC Interacts with RSAD2/viperin (By similarity). Interacts (via C-
CC terminus) with EIF2AK2/PKR (via the kinase catalytic domain) (By
CC similarity). Interacts with ZFAND5. Interacts with IL1RL1. Interacts
CC with TRAFD1. Interacts with AJUBA. Interacts with MAVS/IPS1. Interacts
CC (via TRAF domains) with DYNC2I2 (via WD domains). Interacts with IFIT3
CC (via N-terminus). Interacts with TICAM2. Interacts with CARD14.
CC Interacts with CD40 and MAP3K8; the interaction is required for ERK
CC activation (By similarity). Interacts with TICAM1 and this interaction
CC is enhanced in the presence of WDFY1. Interacts with TANK; this
CC interaction increases in response to DNA damage. Interacts with USP10;
CC this interaction increases in response to DNA damage. Interacts with
CC ZC3H12A; this interaction increases in response to DNA damage and is
CC stimulated by TANK (By similarity). Interacts with WDFY3 (By
CC similarity). Interacts with TRIM13 (By similarity). Interacts with GPS2
CC (By similarity). Interacts (via C-terminus) with SASH1. Interacts with
CC LRRC19. Interacts with IL17RA AND TRAF3IP2. Interacts with TOMM70.
CC Interacts with AMBRA1; interaction is required to mediate 'Lys-63'-
CC linked ubiquitination of ULK1 (By similarity).
CC {ECO:0000250|UniProtKB:P70196, 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-124, Lys-142 and Lys-453 with SUMO1.
CC {ECO:0000250|UniProtKB:Q9Y4K3}.
CC -!- PTM: Polyubiquitinated on Lys-124 by TRAF3IP2; after cell stimulation
CC with IL17A (By similarity). Polyubiquitinated on Lys-124; 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.
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).
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; EU204928; ABY64982.1; -; mRNA.
DR RefSeq; NP_001292890.1; NM_001305961.1.
DR AlphaFoldDB; B6CJY4; -.
DR BMRB; B6CJY4; -.
DR SMR; B6CJY4; -.
DR STRING; 9531.ENSCATP00000012971; -.
DR Ensembl; ENSCATT00000037104; ENSCATP00000012971; ENSCATG00000030633.
DR GeneID; 105586809; -.
DR CTD; 7189; -.
DR GeneTree; ENSGT00940000155426; -.
DR OMA; WMQKNNQ; -.
DR OrthoDB; 918518at2759; -.
DR UniPathway; UPA00143; -.
DR Proteomes; UP000233060; Unplaced.
DR Bgee; ENSCATG00000030633; Expressed in skeletal muscle tissue and 12 other tissues.
DR GO; GO:0035631; C:CD40 receptor complex; IEA:Ensembl.
DR GO; GO:0005938; C:cell cortex; IEA:UniProtKB-SubCell.
DR GO; GO:0009898; C:cytoplasmic side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005811; C:lipid droplet; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0042826; F:histone deacetylase binding; IEA:Ensembl.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0031435; F:mitogen-activated protein kinase kinase kinase binding; IEA:Ensembl.
DR GO; GO:0043422; F:protein kinase B binding; IEA:Ensembl.
DR GO; GO:0047485; F:protein N-terminus binding; IEA:Ensembl.
DR GO; GO:0031996; F:thioesterase binding; IEA:Ensembl.
DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IEA:Ensembl.
DR GO; GO:0031624; F:ubiquitin conjugating enzyme binding; IEA:Ensembl.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IEA:Ensembl.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IEA:Ensembl.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; IEA:Ensembl.
DR GO; GO:0019886; P:antigen processing and presentation of exogenous peptide antigen via MHC class II; IEA:Ensembl.
DR GO; GO:0045453; P:bone resorption; IEA:Ensembl.
DR GO; GO:0048468; P:cell development; IEA:Ensembl.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IEA:UniProtKB-KW.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl.
DR GO; GO:0070498; P:interleukin-1-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0097400; P:interleukin-17-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl.
DR GO; GO:0042475; P:odontogenesis of dentin-containing tooth; IEA:Ensembl.
DR GO; GO:0001503; P:ossification; IEA:Ensembl.
DR GO; GO:0030316; P:osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; ISS:UniProtKB.
DR GO; GO:0032735; P:positive regulation of interleukin-12 production; IEA:Ensembl.
DR GO; GO:0032743; P:positive regulation of interleukin-2 production; IEA:Ensembl.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IEA:Ensembl.
DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IEA:Ensembl.
DR GO; GO:0031666; P:positive regulation of lipopolysaccharide-mediated signaling pathway; IEA:Ensembl.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; ISS:UniProtKB.
DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IEA:Ensembl.
DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IEA:Ensembl.
DR GO; GO:0002726; P:positive regulation of T cell cytokine production; IEA:Ensembl.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IEA:Ensembl.
DR GO; GO:2000679; P:positive regulation of transcription regulatory region DNA binding; IEA:Ensembl.
DR GO; GO:0051865; P:protein autoubiquitination; IEA:Ensembl.
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:0002637; P:regulation of immunoglobulin production; IEA:Ensembl.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0042088; P:T-helper 1 type immune response; IEA:Ensembl.
DR CDD; cd03776; MATH_TRAF6; 1.
DR Gene3D; 2.60.210.10; -; 1.
DR Gene3D; 3.30.40.10; -; 3.
DR InterPro; IPR002083; MATH/TRAF_dom.
DR InterPro; IPR043211; TNF_rcpt-assoc_TRAF.
DR InterPro; IPR012227; TNF_rcpt-assoc_TRAF_met.
DR InterPro; IPR008974; TRAF-like.
DR InterPro; IPR027139; TRAF6.
DR InterPro; IPR037309; TRAF6_MATH.
DR InterPro; IPR041310; TRAF6_Z2.
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; PTHR10131; 1.
DR PANTHER; PTHR10131:SF131; PTHR10131:SF131; 1.
DR Pfam; PF18048; TRAF6_Z2; 1.
DR Pfam; PF02176; zf-TRAF; 1.
DR PIRSF; PIRSF015614; TRAF; 1.
DR SMART; SM00061; MATH; 1.
DR SMART; SM00184; RING; 1.
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..522
FT /note="TNF receptor-associated factor 6"
FT /id="PRO_0000391608"
FT DOMAIN 350..499
FT /note="MATH"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00129"
FT ZN_FING 70..109
FT /note="RING-type; degenerate"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
FT ZN_FING 150..202
FT /note="TRAF-type 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT ZN_FING 203..259
FT /note="TRAF-type 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00207"
FT REGION 1..354
FT /note="Interaction with TAX1BP1"
FT /evidence="ECO:0000250"
FT REGION 355..522
FT /note="Interaction with TANK"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3"
FT COILED 288..348
FT /evidence="ECO:0000255"
FT CROSSLNK 124
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO); alternate"
FT /evidence="ECO:0000250"
FT CROSSLNK 124
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin); alternate"
FT /evidence="ECO:0000250|UniProtKB:Q9Y4K3"
FT CROSSLNK 142
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
FT CROSSLNK 453
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000250"
SQ SEQUENCE 522 AA; 59479 MW; D3538A88F5EFA9B5 CRC64;
MSLLNCENSC GSSQSESDCC VAMASSCSAA TKDDSVGGTA STGNLSSSFM EEIQGYDVEF
DPPLESKYEC PICLMALREA VQTPCGHRFC KACIIKSIRD AGHKCPVDNE ILLENQLFPD
NFAKREILSL MVKCPNEGCL HKMELRHLED HQAHCEFALV DCPQCQRPFQ KFHINIHILK
DCPRRQVSCD NCAALVAFED KEIHDQNCPL ANVICEYCNT ILIREQMPNH YDLDCPTAPI
PCTFSTFGCH EKMQRNHLAR HLQENTQSHM RMLAQAVHSL SLIPDSGYVS EVRNFQETIH
QLEGRLVRQD HQIRELTAKM ETQSTYVSEL KRTIRTLEDK VAEIEAQQCN GIYIWKIGNF
GMHLKCQEEE KPVVIHSPGF YTGKPGYKLC MRLHLQLPTA QRCANYISLF VHTMQGEYDS
HLPWPFQGTI RLTILDQSEA PVRQNHEEIM DAKPDLLAFQ RPTIPRNPKG FGYVTFMHLE
ALRQRTFIKD DTLLVRCEVS TRFDMGSLRR EGFQPRSTDS GV
