TNF receptor-associated factor 6 - Homo sapiens (Human)

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Reviewed, UniProtKB/Swiss-Prot Q9Y4K3 (TRAF6_HUMAN)

Last modified February 9, 2010. Version 111. History...

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

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Names and origin

Protein names

Recommended name:
    TNF receptor-associated factor 6
    EC=6.3.2.-
Alternative name(s):
    E3 ubiquitin-protein ligase TRAF6
    Interleukin-1 signal transducer
    RING finger protein 85

Gene names

Name:	TRAF6
Synonyms:	RNF85

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

Sequence length	522 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level.

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General annotation (Comments)

Function	E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Leads to the activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor.
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Homotrimer. Homooligomer. N-terminal region is dimeric while C-terminal region is trimeric; maybe providing a mode of oligomerization. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK1, IRAK2, IRAK3, IRAK4, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, TRAF, TRAF-interacting protein TRIP and TNF receptor associated protein TTRAP. Interacts with IL17R. Interacts with SQSTM1 bridging NTRK1 and NGFR. Forms a ternary complex with SQSTM1 and PRKCZ By similarity. Interacts with PELI1, PELI2 and PELI3. Binds UBE2V1. Interacts with MAVS/IPS1. Interacts with TAX1BP1. Interacts with IL1RL1. Interacts with TRAFD1. Interacts with ZNF675. Interacts with JUB. Interacts with TICAM1 and TICAM2. Interacts with ZFAND5. Interacts with ARRB1 and ARRB2. Interacts with MAP3K7 and MAP3K7IP1; during IL-1 signaling. Interacts with UBE2N. Interacts with TGFBR1, HDAC1 and RANGAP1. Interacts with AKT1, AKT2 and AKT3.
Subcellular location	Cytoplasm. Cytoplasm › cell cortex. Nucleus. Note: Found in the nuclei of some agressive B-cell lymphoma cell lines as well as in the nuclei of both resting and activated T- and B-lymphocytes. Found in punctate nuclear body protein complexes. Ubiquitination may occur in the cytoplasm and sumoylation in the nucleus.
Tissue specificity	Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
Domain	The coiled coil domain mediates homo- and hetero-oligomerization. The MATH/TRAF domain binds to receptor cytoplasmic domains.
Post-translational modification	Sumoylated on Lys-124, Lys-142 and Lys-453 by SUMO1. Polyubiquitinated on Lys-124; after cell stimulation with IL-1-beta or TGF-beta. This ligand-induced cell stimulation leads to dimerization/oligomerization of TRAF6 molecules, followed by auto-ubiquitination which involves UBE2N and UBE2V1 and leads to TRAF6 activation. This 'Lys-63' site-specific poly-ubiquitination appears to be associated with the activation of signaling molecules. Endogenous autoubiquitination occurs only for the cytoplasmic form.
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.

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Ontologies

Keywords
Biological process	Osteogenesis Ubl conjugation pathway
Cellular component	Cytoplasm Nucleus
Domain	Coiled coil Repeat Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Ligase
PTM	Isopeptide bond Ubl conjugation
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	T cell receptor signaling pathway Inferred from mutant phenotype. Source: UniProtKB activation of NF-kappaB-inducing kinase activity Inferred from mutant phenotype. Source: UniProtKB anti-apoptosis Inferred from Experiment. Source: Reactome apoptosis Inferred from Experiment. Source: Reactome induction of apoptosis by extracellular signals Inferred from Experiment. Source: Reactome membrane protein intracellular domain proteolysis Inferred from Experiment. Source: Reactome modification-dependent protein catabolic process Inferred from electronic annotation. Source: UniProtKB-KW positive regulation of I-kappaB kinase/NF-kappaB cascade Ref.41 Inferred from expression pattern. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Ref.40 Inferred from direct assay. Source: UniProtKB positive regulation of T cell activation Inferred by curator. Source: UniProtKB positive regulation of T cell cytokine production Inferred from mutant phenotype. Source: UniProtKB positive regulation of interleukin-2 production Inferred from mutant phenotype. Source: UniProtKB protein polyubiquitination Ref.44 Inferred from direct assay. Source: UniProtKB
Cellular component	cytosol Ref.14 Inferred from Experiment. Source: Reactome
Molecular function	mitogen-activated protein kinase kinase kinase binding Ref.18 Inferred from physical interaction. Source: UniProtKB protein N-terminus binding Ref.31 Inferred from physical interaction. Source: UniProtKB ubiquitin-protein ligase activity Ref.41 Ref.45 Inferred from direct assay. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

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Binary interactions

With	Entry	#Exp.	IntAct	Notes
ARRB1	P49407	1	EBI-359276,EBI-743313
CD40	P25942	1	EBI-359276,EBI-525714
CTPS	P17812	1	EBI-359276,EBI-1042983
Ecsit	Q9QZH6	1	EBI-359276,EBI-527020	From a different organism.
EDA2R	Q9HAV5	1	EBI-359276,EBI-526033
EIF4E2	O60573	1	EBI-359276,EBI-398610
EPPK1	P58107	1	EBI-359276,EBI-297954
GANAB	Q14697	1	EBI-359276,EBI-348004
IL1R1	P14778	1	EBI-359276,EBI-525905
IL1RL1	Q01638	1	EBI-359276,EBI-993762
IRAK1	P51617	3	EBI-359276,EBI-358664
IRAK2	O43187	1	EBI-359276,EBI-447733
IRAK3	Q9Y616	1	EBI-359276,EBI-447690
MAP3K14	Q99558	1	EBI-359276,EBI-358011
MCM7	P33993	1	EBI-359276,EBI-355924
MTHFD1	P11586	1	EBI-359276,EBI-709638
NASP	P49321	1	EBI-359276,EBI-716205
OTUD7B	Q6GQQ9	1	EBI-359276,EBI-527784
PAICS	P22234	1	EBI-359276,EBI-712261
PELI3	Q8N2H9-1	1	EBI-359276,EBI-448466
PELI3	Q8N2H9-2	1	EBI-359276,EBI-448472
PFAS	O15067	1	EBI-359276,EBI-1052653
TARS	P26639	1	EBI-359276,EBI-1042683
TAX1BP1	Q86VP1	1	EBI-359276,EBI-529518
TICAM2	Q86XR7	1	EBI-359276,EBI-525927
TJP2	Q9UDY2	1	EBI-359276,EBI-1042602
TNFAIP3	P21580	1	EBI-359276,EBI-527670
TNFRSF11A	Q9Y6Q6	1	EBI-359276,EBI-525675
TRAFD1	O14545	1	EBI-359276,EBI-1396921
UBE2D1	P51668	1	EBI-359276,EBI-743540
UBE2D2	P62837	1	EBI-359276,EBI-347677
UBE2D3	P61077	1	EBI-359276,EBI-348268
UBE2E1	P51965	1	EBI-359276,EBI-348546
UBE2N	P61088	1	EBI-359276,EBI-1052908
VARS	P26640	1	EBI-359276,EBI-355765
VCP	Q5VYM0	1	EBI-359276,EBI-1046421
VDAC1	P21796	1	EBI-359276,EBI-354158
ZNF675	Q8TD23	3	EBI-359276,EBI-528190
ZRANB1	Q9UGI0	1	EBI-359276,EBI-527853

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Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 522

522

TNF receptor-associated factor 6

PRO_0000056407

Regions

Domain

350 – 499

150

MATH

Zinc finger

70 – 109

RING-type

Zinc finger

150 – 202

TRAF-type 1

Zinc finger

203 – 259

TRAF-type 2

Region

1 – 354

354

Interaction with TAX1BP1

Coiled coil

288 – 348

Potential

Amino acid modifications

Cross-link

124

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO); alternate

Cross-link

124

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin); alternate

Cross-link

142

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)

Cross-link

453

Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO)

Experimental info

Mutagenesis

D → K: Loss of interaction with UBE2N.

Mutagenesis

C → A: Loss of ligase activity, autoubiquitination and signaling capacity.

Mutagenesis

I → D: Loss of interaction with UBE2N.

Mutagenesis

L → E or K: Loss of interaction with UBE2N.

Mutagenesis

R → A: Loss of TRAF6 homodimerization and impaired polyubiquitin synthesis. Loss of TRAF6 homodimerization and impaired polyubiquitin synthesis; when associated with A-122.

Mutagenesis

118

F → A: Loss of TRAF6 homodimerization and impaired polyubiquitin synthesis.

Mutagenesis

118

F → W: Partially impaired polyubiquitin synthesis.

Mutagenesis

118

F → Y: Partially impaired polyubiquitin synthesis.

Mutagenesis

122

F → A: Loss of TRAF6 homodimerization and partially impaired polyubiquitin synthesis. Loss of TRAF6 homodimerization and impaired polyubiquitin synthesis; when associated with A-88.

Mutagenesis

124

K → R: Loss of SUMO1-modification and c-myb-mediated transcriptional repressive activation.

Mutagenesis

142

K → R: Loss of SUMO1-modification and c-myb-mediated transcriptional repressive activation.

Mutagenesis

453

K → R: Loss of SUMO1-modification and c-myb-mediated transcriptional repressive activation.

Sequence conflict

S → F in AAH31052. Ref.6

Secondary structure

522

Helix Strand Turn

Details...

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Sequences

Sequence

Length

Mass (Da)

Tools

Q9Y4K3-1 [UniParc].

Last modified November 1, 1999. Version 1.
Checksum: 5AB9C255CCFEE749
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FASTA

522

59,573

        10         20         30         40         50         60 
MSLLNCENSC GSSQSESDCC VAMASSCSAV TKDDSVGGTA STGNLSSSFM EEIQGYDVEF 

        70         80         90        100        110        120 
DPPLESKYEC PICLMALREA VQTPCGHRFC KACIIKSIRD AGHKCPVDNE ILLENQLFPD 

       130        140        150        160        170        180 
NFAKREILSL MVKCPNEGCL HKMELRHLED HQAHCEFALM DCPQCQRPFQ KFHINIHILK 

       190        200        210        220        230        240 
DCPRRQVSCD NCAASMAFED KEIHDQNCPL ANVICEYCNT ILIREQMPNH YDLDCPTAPI 

       250        260        270        280        290        300 
PCTFSTFGCH EKMQRNHLAR HLQENTQSHM RMLAQAVHSL SVIPDSGYIS EVRNFQETIH 

       310        320        330        340        350        360 
QLEGRLVRQD HQIRELTAKM ETQSMYVSEL KRTIRTLEDK VAEIEAQQCN GIYIWKIGNF 

       370        380        390        400        410        420 
GMHLKCQEEE KPVVIHSPGF YTGKPGYKLC MRLHLQLPTA QRCANYISLF VHTMQGEYDS 

       430        440        450        460        470        480 
HLPWPFQGTI RLTILDQSEA PVRQNHEEIM DAKPELLAFQ RPTIPRNPKG FGYVTFMHLE 

       490        500        510        520 
ALRQRTFIKD DTLLVRCEVS TRFDMGSLRR EGFQPRSTDA GV

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References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"TRAF6 is a signal transducer for interleukin-1." Cao Z., Xiong J., Takeuchi M., Kurama T., Goeddel D.V. Nature 383:443-446(1996) [PubMed: 8837778] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTION WITH IRAK1.
[2]	SeattleSNPs variation discovery resource Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. Sugano S. Nat. Genet. 36:40-45(2004) [PubMed: 14702039] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Trachea.
[4]	"Human chromosome 11 DNA sequence and analysis including novel gene identification." Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K., Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T., Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G. Sakaki Y. Nature 440:497-500(2006) [PubMed: 16554811] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Testis.
[7]	"MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1." Malinin N.L., Boldin M.P., Kovalenko A.V., Wallach D. Nature 385:540-544(1997) [PubMed: 9020361] [Abstract] Cited for: INTERACTION WITH MAP3K14.
[8]	"IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling." Muzio M., Ni J., Feng P., Dixit V.M. Science 278:1612-1615(1997) [PubMed: 9374458] [Abstract] Cited for: INTERACTION WITH IRAK2.
[9]	"RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase." McCarthy J.V., Ni J., Dixit V.M. J. Biol. Chem. 273:16968-16975(1998) [PubMed: 9642260] [Abstract] Cited for: INTERACTION WITH RIPK2.
[10]	"The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor." Wong B.R., Josien R., Lee S.Y., Vologodskaia M., Steinman R.M., Choi Y. J. Biol. Chem. 273:28355-28359(1998) [PubMed: 9774460] [Abstract] Cited for: INTERACTION WITH TNFRSF11A.
[11]	"Tumor necrosis factor receptor-associated factor 6 (TRAF6) stimulates extracellular signal-regulated kinase (ERK) activity in CD40 signaling along a ras-independent pathway." Kashiwada M., Shirakata Y., Inoue J., Nakano H., Okazaki K., Okumura K., Yamamoto T., Nagaoka H., Takemori T. J. Exp. Med. 187:237-244(1998) [PubMed: 9432981] [Abstract] Cited for: INTERACTION WITH TNFRSF5.
[12]	"ASK1 is essential for JNK/SAPK activation by TRAF2." Nishitoh H., Saitoh M., Mochida Y., Takeda K., Nakano H., Rothe M., Miyazono K., Ichijo H. Mol. Cell 2:389-395(1998) [PubMed: 9774977] [Abstract] Cited for: INTERACTION WITH MAP3K5.
[13]	"Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain." Baud V., Liu Z.-G., Bennett B., Suzuki N., Xia Y., Karin M. Genes Dev. 13:1297-1308(1999) [PubMed: 10346818] [Abstract] Cited for: INTERACTION WITH MAP3K1.
[14]	"Association of the p75 neurotrophin receptor with TRAF6." Khursigara G., Orlinick J.R., Chao M.V. J. Biol. Chem. 274:2597-2600(1999) [PubMed: 9915784] [Abstract] Cited for: INTERACTION WITH NGFR.
[15]	"IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family." Wesche H., Gao X., Li X., Kirschning C.J., Stark G.R., Cao Z. J. Biol. Chem. 274:19403-19410(1999) [PubMed: 10383454] [Abstract] Cited for: INTERACTION WITH IRAK3.
[16]	"TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction." Ye X., Mehlen P., Rabizadeh S., VanArsdale T., Zhang H., Shin H., Wang J.J.L., Leo E., Zapata J.M., Hauser C.A., Reed J.C., Bredesen D.E. J. Biol. Chem. 274:30202-30208(1999) [PubMed: 10514511] [Abstract] Cited for: INTERACTION WITH NGFR.
[17]	"TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src." Wong B.R., Besser D., Kim N., Arron J.R., Vologodskaia M., Hanafusa H., Choi Y. Mol. Cell 4:1041-1049(1999) [PubMed: 10635328] [Abstract] Cited for: INTERACTION WITH TNFRSF11A AND CSK.
[18]	"The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway." Ninomiya-Tsuji J., Kishimoto K., Hiyama A., Inoue J., Cao Z., Matsumoto K. Nature 398:252-256(1999) [PubMed: 10094049] [Abstract] Cited for: INTERACTION WITH MAP3K7 AND MAP3K7IP1.
[19]	"Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)." Hoeflich K.P., Yeh W.C., Yao Z., Mak T.W., Woodgett J.R. Oncogene 18:5814-5820(1999) [PubMed: 10523862] [Abstract] Cited for: INTERACTION WITH MAP3K5.
[20]	"Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain." Deng L., Wang C., Spencer E., Yang L., Braun A., You J., Slaughter C., Pickart C., Chen Z.J. Cell 103:351-361(2000) [PubMed: 11057907] [Abstract] Cited for: INTERACTION WITH UBE2V1, FUNCTION AS A E3 UBIQUITIN LIGASE.
[21]	"TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation." Pype S., Declercq W., Ibrahimi A., Michiels C., Van Rietschoten J.G.I., Dewulf N., de Boer M., Vandenabeele P., Huylebroeck D., Remacle J.E. J. Biol. Chem. 275:18586-18593(2000) [PubMed: 10764746] [Abstract] Cited for: INTERACTION WITH TTRAP.
[22]	"B cell maturation protein is a receptor for the tumor necrosis factor family member TALL-1." Shu H.-B., Johnson H. Proc. Natl. Acad. Sci. U.S.A. 97:9156-9161(2000) [PubMed: 10908663] [Abstract] Cited for: INTERACTION WITH TNFRSF17.
[23]	"T6BP, a TRAF6-interacting protein involved in IL-1 signaling." Ling L., Goeddel D.V. Proc. Natl. Acad. Sci. U.S.A. 97:9567-9572(2000) [PubMed: 10920205] [Abstract] Cited for: INTERACTION WITH TAX1BP1.
[24]	"TAK1 is a ubiquitin-dependent kinase of MKK and IKK." Wang C., Deng L., Hong M., Akkaraju G.R., Inoue J., Chen Z.J. Nature 412:346-351(2001) [PubMed: 11460167] [Abstract] Cited for: UBIQUITINATION.
[25]	"A novel zinc finger protein that inhibits osteoclastogenesis and the function of tumor necrosis factor receptor-associated factor 6." Shin J.N., Kim I., Lee J.S., Koh G.Y., Lee Z.H., Kim H.-H. J. Biol. Chem. 277:8346-8353(2002) [PubMed: 11751921] [Abstract] Cited for: INTERACTION WITH ZNF675.
[26]	"IRAK4: a novel member of the IRAK family with the properties of an IRAK-kinase." Li S., Strelow A., Fontana E.J., Wesche H. Proc. Natl. Acad. Sci. U.S.A. 99:5567-5572(2002) [PubMed: 11960013] [Abstract] Cited for: INTERACTION WITH IRAK4.
[27]	"Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex." Jiang Z., Johnson H.J., Nie H., Qin J., Bird T.A., Li X. J. Biol. Chem. 278:10952-10956(2003) [PubMed: 12496252] [Abstract] Cited for: INTERACTION WITH PELI1.
[28]	"Pellino2 activates the mitogen activated protein kinase pathway." Jensen L.E., Whitehead A.S. FEBS Lett. 545:199-202(2003) [PubMed: 12804775] [Abstract] Cited for: INTERACTION WITH PELI1 AND PELI2.
[29]	"TIRP, a novel Toll/interleukin-1 receptor (TIR) domain-containing adapter protein involved in TIR signaling." Bin L.-H., Xu L.-G., Shu H.-B. J. Biol. Chem. 278:24526-24532(2003) [PubMed: 12721283] [Abstract] Cited for: INTERACTION WITH TICAM2.
[30]	"Pellino3, a novel member of the Pellino protein family, promotes activation of c-Jun and Elk-1 and may act as a scaffolding protein." Jensen L.E., Whitehead A.S. J. Immunol. 171:1500-1506(2003) [PubMed: 12874243] [Abstract] Cited for: INTERACTION WITH PELI3.
[31]	"Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling." Sato S., Sugiyama M., Yamamoto M., Watanabe Y., Kawai T., Takeda K., Akira S. J. Immunol. 171:4304-4310(2003) [PubMed: 14530355] [Abstract] Cited for: INTERACTION WITH TICAM1.
[32]	"Mechanisms of the TRIF-induced interferon-stimulated response element and NF-kappaB activation and apoptosis pathways." Han K.J., Su X., Xu L.-G., Bin L.H., Zhang J., Shu H.-B. J. Biol. Chem. 279:15652-15661(2004) [PubMed: 14739303] [Abstract] Cited for: INTERACTION WITH TICAM1.
[33]	"ZNF216 is an A20-like and IkappaB kinase gamma-interacting inhibitor of NFkappaB activation." Huang J., Teng L., Li L., Liu T., Li L., Chen D., Xu L.-G., Zhai Z., Shu H.-B. J. Biol. Chem. 279:16847-16853(2004) [PubMed: 14754897] [Abstract] Cited for: INTERACTION WITH ZFAND5.
[34]	"Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta." Jiang Z., Mak T.W., Sen G., Li X. Proc. Natl. Acad. Sci. U.S.A. 101:3533-3538(2004) [PubMed: 14982987] [Abstract] Cited for: INTERACTION WITH TICAM1.
[35]	"Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3." Seth R.B., Sun L., Ea C.-K., Chen Z.J. Cell 122:669-682(2005) [PubMed: 16125763] [Abstract] Cited for: INTERACTION WITH MAVS.
[36]	"IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST 2 and induces T helper type 2-associated cytokines." Schmitz J., Owyang A., Oldham E., Song Y., Murphy E., McClanahan T.K., Zurawski G., Moshrefi M., Qin J., Li X., Gorman D.M., Bazan J.F., Kastelein R.A. Immunity 23:479-490(2005) [PubMed: 16286016] [Abstract] Cited for: INTERACTION WITH IL1RL1.
[37]	"FLN29, a novel interferon- and LPS-inducible gene acting as a negative regulator of toll-like receptor signaling." Mashima R., Saeki K., Aki D., Minoda Y., Takaki H., Sanada T., Kobayashi T., Aburatani H., Yamanashi Y., Yoshimura A. J. Biol. Chem. 280:41289-41297(2005) [PubMed: 16221674] [Abstract] Cited for: INTERACTION WITH TRAFD1.
[38]	"VISA is an adapter protein required for virus-triggered IFN-beta Signaling." Xu L.-G., Wang Y.-Y., Han K.-J., Li L.-Y., Zhai Z., Shu H.-B. Mol. Cell 19:727-740(2005) [PubMed: 16153868] [Abstract] Cited for: INTERACTION WITH MAVS.
[39]	"The LIM protein Ajuba influences interleukin-1-induced NF-kappaB activation by affecting the assembly and activity of the protein kinase Czeta/p62/TRAF6 signaling complex." Feng Y., Longmore G.D. Mol. Cell. Biol. 25:4010-4022(2005) [PubMed: 15870274] [Abstract] Cited for: INTERACTION WITH JUB.
[40]	"Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling." Wang Y., Tang Y., Teng L., Wu Y., Zhao X., Pei G. Nat. Immunol. 7:139-147(2006) [PubMed: 16378096] [Abstract] Cited for: FUNCTION IN TRANSCRIPTIONAL ACTIVATION OF NF-KAPPA-B AND JUN, INTERACTION WITH ARBB1 AND ARBB2.
[41]	"Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation." Lamothe B., Besse A., Campos A.D., Webster W.K., Wu H., Darnay B.G. J. Biol. Chem. 282:4102-4112(2007) [PubMed: 17135271] [Abstract] Cited for: MUTAGENESIS OF CYS-70 AND LYS-124, UBIQUITINATION AT LYS-124, FUNCTION.
[42]	"Nuclear tumor necrosis factor receptor-associated factor 6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through small ubiquitin-related modifier-1 modification." Pham L.V., Zhou H.J., Lin-Lee Y.C., Tamayo A.T., Yoshimura L.C., Fu L., Darnay B.G., Ford R.J. J. Biol. Chem. 283:5081-5089(2008) [PubMed: 18093978] [Abstract] Cited for: SUBCELLULAR LOCATION, FUNCTION, SUMOYLATION AT LYS-124; LYS-142 AND LYS-453, UBIQUITINATION, INTERACTION WITH HDAC1 AND RANGAP1, MUTAGENESIS OF LYS-124; LYS-142 AND LYS-453.
[43]	"The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner." Sorrentino A., Thakur N., Grimsby S., Marcusson A., von Bulow V., Schuster N., Zhang S., Heldin C.H., Landstrom M. Nat. Cell Biol. 10:1199-1207(2008) [PubMed: 18758450] [Abstract] Cited for: FUNCTION, INTERACTION WITH TGFBR1, UBIQUITINATION.
[44]	"Direct activation of protein kinases by unanchored polyubiquitin chains." Xia Z.-P., Sun L., Chen X., Pineda G., Jiang X., Adhikari A., Zeng W., Chen Z.J. Nature 461:114-119(2009) [PubMed: 19675569] [Abstract] Cited for: FUNCTION, UBIQUITINATION.
[45]	"The E3 ligase TRAF6 regulates Akt ubiquitination and activation." Yang W.-L., Wang J., Chan C.-H., Lee S.-W., Campos A.D., Lamothe B., Hur L., Grabiner B.C., Lin X., Darnay B.G., Lin H.-K. Science 325:1134-1138(2009) [PubMed: 19713527] [Abstract] Cited for: FUNCTION.
[46]	"Distinct molecular mechanism for initiating TRAF6 signalling." Ye H., Arron J.R., Lamothe B., Cirilli M., Kobayashi T., Shevde N.K., Segal D., Dzivenu O.K., Vologodskaia M., Yim M., Du K., Singh S., Pike J.W., Darnay B.G., Choi Y., Wu H. Nature 418:443-447(2002) [PubMed: 12140561] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 347-506 OF APOPROTEIN AND IN COMPLEXES WITH TNFRSF5 AND TNFRSF11A PEPTIDES, FUNCTION, SUBUNIT.
[47]	"Structure, interactions, and dynamics of the RING domain from human TRAF6." Mercier P., Lewis M.J., Hau D.D., Saltibus L.F., Xiao W., Spyracopoulos L. Protein Sci. 16:602-614(2007) [PubMed: 17327397] [Abstract] Cited for: STRUCTURE BY NMR OF 63-124 IN COMPLEX WITH ZINC IONS, INTERACTION WITH UBE2N.
[48]	"Solution structure of the RING domain of the human TNF receptor-associated factor 6 protein." RIKEN structural genomics initiative (RSGI) Submitted (MAR-2008) to the PDB data bank Cited for: STRUCTURE BY NMR OF 43-128.
[49]	"E2 interaction and dimerization in the crystal structure of TRAF6." Yin Q., Lin S.C., Lamothe B., Lu M., Lo Y.C., Hura G., Zheng L., Rich R.L., Campos A.D., Myszka D.G., Lenardo M.J., Darnay B.G., Wu H. Nat. Struct. Mol. Biol. 16:658-666(2009) [PubMed: 19465916] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 50-211 IN COMPLEXES WITH ZINC IONS AND UBE2N, SUBUNIT, FUNCTION, AUTOUBIQUITINATION, MUTAGENESIS OF ASP-57; CYS-70; ILE-72; LEU-74; ARG-88; PHE-118; PHE-122 AND LYS-124, ZINC-FINGER.
+	Additional computationally mapped references.

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Web resources

SeattleSNPs

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Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U78798 mRNA. Translation: AAB38751.1.
AY228337 Genomic DNA. Translation: AAO38054.1.
AK292978 mRNA. Translation: BAF85667.1.
AC009656 Genomic DNA. No translation available.
AC061999 Genomic DNA. No translation available.
CH471064 Genomic DNA. Translation: EAW68119.1.
BC031052 mRNA. Translation: AAH31052.1.

IPI

IPI00743663.

PIR

S71821.

RefSeq

NP_004611.1.
NP_665802.1.

UniGene

Hs.591983

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1LB4	X-ray	2.40	A	348-504	[»]
1LB5	X-ray	2.40	A	347-504	[»]
1LB6	X-ray	1.80	A	347-504	[»]
2ECI	NMR	-	A	47-128	[»]
2JMD	NMR	-	A	63-124	[»]
3HCS	X-ray	2.20	A/B	50-211	[»]
3HCT	X-ray	2.10	A	50-159	[»]
3HCU	X-ray	2.60	A/C	50-159	[»]

SMR

Q9Y4K3. Positions 43-128, 147-212, 202-269, 297-502.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-27515N.

IntAct

Q9Y4K3. 351 interactions.

STRING

Q9Y4K3.

PTM databases

PhosphoSite

Q9Y4K3.

Proteomic databases

PRIDE

Q9Y4K3.

Genome annotation databases

Ensembl

ENST00000313105; ENSP00000316840; ENSG00000175104; Homo sapiens. [Genome view]
ENST00000348124; ENSP00000337853; ENSG00000175104; Homo sapiens. [Genome view]

GeneID

7189.

KEGG

hsa:7189.

UCSC

uc001mwr.1. human.

Organism-specific databases

CTD

7189.

GeneCards

GC11M036467.

H-InvDB

HIX0009567.

HGNC

HGNC:12036. TRAF6.

HPA

CAB004605.
HPA019805.
HPA020599.

MIM

602355. gene.

PharmGKB

PA36713.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG11906.

HOGENOM

HBG281555.

HOVERGEN

Q9Y4K3.

InParanoid

Q9Y4K3.

OMA

SAQRCAN.

OrthoDB

EOG9W9MQ1.

PhylomeDB

Q9Y4K3.

Enzyme and pathway databases

Pathway_Interaction_DB

bcr_5pathway. BCR signaling pathway.
nfkappabcanonicalpathway. Canonical NF-kappaB pathway.
il1pathway. IL1-mediated signaling events.
p38_mkk3_6pathway. p38 MAPK signaling pathway.
p75ntrpathway. p75(NTR)-mediated signaling.
p38alphabetapathway. Regulation of p38-alpha and p38-beta.
tcrpathway. TCR signaling in naive CD4+ T cells.
cd8tcrpathway. TCR signaling in naive CD8+ T cells.

Reactome

REACT_11061. Signalling by NGF.
REACT_6900. Signaling in Immune system.

Gene expression databases

ArrayExpress

Q9Y4K3.

Bgee

Q9Y4K3.

CleanEx

HS_TRAF6.

Genevestigator

Q9Y4K3.

GermOnline

ENSG00000175104. Homo sapiens.

Family and domain databases

InterPro

IPR002083. MATH.
IPR012227. TNF_recpt_TRAF.
IPR008974. TRAF-like.
IPR013322. TRAF-type.
IPR018957. Znf_C3HC4_RING-type.
IPR001841. Znf_RING.
IPR017907. Znf_RING_CS.
IPR001293. Znf_TRAF.
[Graphical view]

Gene3D

G3DSA:2.60.210.10. TRAF-type. 1 hit.

Pfam

PF00917. MATH. 1 hit.
PF00097. zf-C3HC4. 1 hit.
[Graphical view]

PIRSF

PIRSF015614. TRAF. 1 hit.

SMART

SM00061. MATH. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]

PROSITE

PS50144. MATH. 1 hit.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
PS50145. ZF_TRAF. 2 hits.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

28192.

SOURCE

Search...

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Entry information

Entry name

TRAF6_HUMAN

Accession

Primary (citable) accession number: Q9Y4K3
Secondary accession number(s): A6NKI7, A8KAB3, Q8NEH5

Entry history

Integrated into UniProtKB/Swiss-Prot:	May 9, 2003
Last sequence update:	November 1, 1999
Last modified:	February 9, 2010
This is version 111 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

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Relevant documents

Human chromosome 11

Human chromosome 11: entries, gene names and cross-references to MIM

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

PATHWAY comments

Index of metabolic and biosynthesis pathways

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

SIMILARITY comments

Index of protein domains and families

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Sequence annotation (Features)

Molecule processing

Regions

Amino acid modifications

Experimental info

Secondary structure

Sequences

References

Web resources

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Proteomic databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other Resources

Entry information

Relevant documents