Reviewed, UniProtKB/Swiss-Prot Q9Y4K3 (TRAF6_HUMAN)

Names and origin

Protein names

Recommended name:
    TNF receptor-associated factor 6
Alternative name(s):
    Interleukin-1 signal transducer
    RING finger protein 85

Gene names

Name:	TRAF6
Synonyms:	RNF85

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

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

Protein attributes

Sequence length	522 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Adapter protein and signal transducer that links members of the tumor necrosis factor receptor family to different signaling pathways by association with the receptor cytoplasmic domain and kinases. Also involved in the IL-1 signaling pathway via MYD88 and IRAK kinases. Seems to be involved in IL-17 signaling By similarity. Mediates activation of NF-kappa-B and JNK. May function as an E3 ubiquitin ligase.
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Homotrimer Probable. Binds to TNFRSF5/CD40 and TNFRSF11A/RANK. Associates with NGFR, TNFRSF17, IRAK1, IRAK2, IRAK3, IRAK4, RIPK2, MAP3K1, MAP3K5, MAP3K14, CSK, and TRAF-interacting protein TRIP and TRAF 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.
Subcellular location	CytoplasmProbable.
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	Polyubiquitinated By similarity.
Sequence similarities	Contains 1 MATH domain. Contains 1 RING-type zinc finger. Contains 2 TRAF-type zinc fingers.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cytoplasm
Domain	Coiled coil Repeat Zinc-finger
Ligand	Metal-binding Zinc
PTM	Ubl conjugation
Technical term	3D-structure
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 positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from expression pattern. 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 Inferred from direct assay. Source: UniProtKB regulation of apoptosis Inferred from electronic annotation. Source: InterPro ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: UniProtKB-KW
Cellular component	cytosol Inferred from Experiment. Source: Reactome
Molecular function	protein binding Ref.14 Ref.21 Ref.22 Ref.26 Ref.27 Ref.31 Ref.32 Ref.35 Inferred from physical interaction. Source: UniProtKB ubiquitin-protein ligase activity Inferred from direct assay. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
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
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

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

40

RING-type

Zinc finger

150 – 202

53

TRAF-type 1

Zinc finger

203 – 259

57

TRAF-type 2

Region

1 – 354

354

Interaction with TAX1BP1

Coiled coil

288 – 348

61

Potential

Experimental info

Sequence conflict

12

1

S → F in AAH31052. Ref.2

Secondary structure

1

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522

Helix Strand Turn

Details...

Turn

71 – 73

3

Beta strand

81 – 83

3

Turn

84 – 86

3

Beta strand

87 – 89

3

Helix

91 – 100

10

Turn

106 – 108

3

Beta strand

350 – 357

8

Helix

360 – 368

9

Beta strand

373 – 376

4

Beta strand

380 – 386

7

Beta strand

388 – 395

8

Beta strand

401 – 403

3

Beta strand

406 – 413

8

Helix

419 – 421

3

Beta strand

428 – 434

7

Helix

440 – 442

3

Beta strand

446 – 451

6

Beta strand

471 – 478

8

Helix

479 – 484

6

Beta strand

492 – 501

10

Sequences

	Sequence		Length	Mass (Da)
	Q9Y4K3-1 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: 5AB9C255CCFEE749	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

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], INTERACTION WITH IRAK1.
[2]	SeattleSNPs program for genomic applications Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"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.
[4]	"The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators." Wajant H., Henkler F., Scheurich P. Cell. Signal. 13:389-400(2001) [PubMed: 11384837] [Abstract] Cited for: REVIEW.
[5]	"Tumor necrosis factor receptor-associated factors (TRAFs)." Bradley J.R., Pober J.S. Oncogene 20:6482-6491(2001) [PubMed: 11607847] [Abstract] Cited for: REVIEW.
[6]	"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.
[7]	"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.
[8]	"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.
[9]	"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.
[10]	"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.
[11]	"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.
[12]	"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.
[13]	"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.
[14]	"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.
[15]	"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.
[16]	"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.
[17]	"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.
[18]	"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.
[19]	"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.
[20]	"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.
[21]	"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.
[22]	"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.
[23]	"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.
[24]	"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.
[25]	"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.
[26]	"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.
[27]	"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.
[28]	"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.
[29]	"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.
[30]	"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.
[31]	"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.
[32]	"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.
[33]	"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.
[34]	"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.
[35]	"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 (2.4 ANGSTROMS) OF 347-506 IN COMPLEX WITH TNFRSF11A, X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 347-506 IN COMPLEX WITH TNFRSF5.
+	Additional computationally mapped references.

Web resources

SeattleSNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

U78798 mRNA. Translation: AAB38751.1.
AY228337 Genomic DNA. Translation: AAO38054.1.
BC031052 mRNA. Translation: AAH31052.1.

PIR

S71821.

RefSeq

NP_004611.1.
NP_665802.1.

UniGene

Hs.591983

3D structure databases

PDBMSD

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	43-128	[»]
2JMD	NMR