Full text data of TRADD
TRADD
[Confidence: low (only semi-automatic identification from reviews)]
Tumor necrosis factor receptor type 1-associated DEATH domain protein; TNFR1-associated DEATH domain protein (TNFRSF1A-associated via death domain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Tumor necrosis factor receptor type 1-associated DEATH domain protein; TNFR1-associated DEATH domain protein (TNFRSF1A-associated via death domain)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q15628
ID TRADD_HUMAN Reviewed; 312 AA.
AC Q15628; B2RDS3; Q52NZ1;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 15-JUL-1999, sequence version 2.
DT 22-JAN-2014, entry version 135.
DE RecName: Full=Tumor necrosis factor receptor type 1-associated DEATH domain protein;
DE Short=TNFR1-associated DEATH domain protein;
DE AltName: Full=TNFRSF1A-associated via death domain;
GN Name=TRADD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7758105; DOI=10.1016/0092-8674(95)90070-5;
RA Hsu H., Xiong J., Goeddel D.V.;
RT "The TNF receptor 1-associated protein TRADD signals cell death and
RT NF-kappa B activation.";
RL Cell 81:495-504(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Scheuerpflug C.G., Dechant M., Fellenberg J., Ewerbeck V.,
RA Debatin K.M.;
RT "Sequence, genomic organisation, and mutation analysis of the human
RT TRADD gene in childhood B- and T-lineage acute lymphoblastic leukemia
RT and ALPS.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Kaiser C., Kohstall B., Kieser A.;
RT "Cloning of the human TRADD gene locus.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary gland;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP INTERACTION WITH RIPK1.
RX PubMed=8612133; DOI=10.1016/S1074-7613(00)80252-6;
RA Hsu H., Huang J., Shu H.-B., Baichwal V.R., Goeddel D.V.;
RT "TNF-dependent recruitment of the protein kinase RIP to the TNF
RT receptor-1 signaling complex.";
RL Immunity 4:387-396(1996).
RN [10]
RP INTERACTION WITH SQSTM1.
RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044;
RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.;
RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB
RT activation.";
RL EMBO J. 18:3044-3053(1999).
RN [11]
RP INTERACTION WITH HIPK2.
RX PubMed=11032752; DOI=10.1006/bbrc.2000.3700;
RA Li X., Wang Y., Debatin K.-M., Hug H.;
RT "The serine/threonine kinase HIPK2 interacts with TRADD, but not with
RT CD95 or TNF-R1 in 293T cells.";
RL Biochem. Biophys. Res. Commun. 277:513-517(2000).
RN [12]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH KRT14 AND KRT18.
RX PubMed=11684708; DOI=10.1083/jcb.200103078;
RA Inada H., Izawa I., Nishizawa M., Fujita E., Kiyono T., Takahashi T.,
RA Momoi T., Inagaki M.;
RT "Keratin attenuates tumor necrosis factor-induced cytotoxicity through
RT association with TRADD.";
RL J. Cell Biol. 155:415-426(2001).
RN [13]
RP INTERACTION WITH DAB2IP.
RX PubMed=15310755; DOI=10.1074/jbc.M407617200;
RA Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W.;
RT "AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-
RT induced ASK1-JNK activation.";
RL J. Biol. Chem. 279:44955-44965(2004).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP STRUCTURE BY NMR OF 1-179.
RX PubMed=10911999; DOI=10.1016/S1097-2765(00)80270-1;
RA Tsao D.H., McDonagh T., Telliez J.-B., Hsu S., Malakian K., Xu G.Y.,
RA Lin L.L.;
RT "Solution structure of N-TRADD and characterization of the interaction
RT of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway.";
RL Mol. Cell 5:1051-1057(2000).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-179 IN COMPLEX WITH TRAF2.
RX PubMed=10892748; DOI=10.1016/S0092-8674(00)80889-2;
RA Park Y.C., Ye H., Hsia C., Segal D., Rich R.L., Liou H.C.,
RA Myszka D.G., Wu H.;
RT "A novel mechanism of TRAF signaling revealed by structural and
RT functional analyses of the TRADD-TRAF2 interaction.";
RL Cell 101:777-787(2000).
CC -!- FUNCTION: The nuclear form acts as a tumor suppressor by
CC preventing ubiquitination and degradation of isoform p19ARF/ARF of
CC CDKN2A by TRIP12: acts by interacting with TRIP12, leading to
CC disrupt interaction between TRIP12 and isoform p19ARF/ARF of
CC CDKN2A (By similarity). Adapter molecule for TNFRSF1A/TNFR1 that
CC specifically associates with the cytoplasmic domain of activated
CC TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression
CC of TRADD leads to two major TNF-induced responses, apoptosis and
CC activation of NF-kappa-B.
CC -!- SUBUNIT: Interacts with TRIP12 (By similarity). Heterodimer with
CC TNFRSF1A/TNFR1. Interacts with DAB2IP, FADD, HIPK2, KRT14, KRT16,
CC KRT17, KRT18, RIPK1, SQSTM1, TRAF1, TRAF2 and TRPC4AP.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-359215, EBI-359215;
CC P05783:KRT18; NbExp=11; IntAct=EBI-359215, EBI-297888;
CC P19438:TNFRSF1A; NbExp=11; IntAct=EBI-359215, EBI-299451;
CC Q12933:TRAF2; NbExp=2; IntAct=EBI-359215, EBI-355744;
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). Cytoplasm (By
CC similarity). Cytoplasm, cytoskeleton. Note=Shuttles between the
CC cytoplasm and the nucleus (By similarity).
CC -!- TISSUE SPECIFICITY: Found in all examined tissues.
CC -!- DOMAIN: Requires the intact death domain to associate with
CC TNFRSF1A/TNFR1.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA98482.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/tradd/";
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DR EMBL; L41690; AAA98482.1; ALT_INIT; mRNA.
DR EMBL; AJ311614; CAC38018.2; -; Genomic_DNA.
DR EMBL; AJ311615; CAC38018.2; JOINED; Genomic_DNA.
DR EMBL; AJ311616; CAC38018.2; JOINED; Genomic_DNA.
DR EMBL; AY995114; AAX89407.1; -; Genomic_DNA.
DR EMBL; BT006934; AAP35580.1; -; mRNA.
DR EMBL; AY575851; AAS68637.1; -; Genomic_DNA.
DR EMBL; AK315654; BAG38020.1; -; mRNA.
DR EMBL; CH471092; EAW83081.1; -; Genomic_DNA.
DR EMBL; BC004491; AAH04491.1; -; mRNA.
DR PIR; A56911; A56911.
DR RefSeq; NP_003780.1; NM_003789.3.
DR UniGene; Hs.460996; -.
DR PDB; 1F2H; NMR; -; A=1-169.
DR PDB; 1F3V; X-ray; 2.00 A; A=1-179.
DR PDBsum; 1F2H; -.
DR PDBsum; 1F3V; -.
DR ProteinModelPortal; Q15628; -.
DR SMR; Q15628; 1-169.
DR DIP; DIP-285N; -.
DR IntAct; Q15628; 14.
DR MINT; MINT-99115; -.
DR STRING; 9606.ENSP00000341268; -.
DR PhosphoSite; Q15628; -.
DR DMDM; 6094511; -.
DR PaxDb; Q15628; -.
DR PRIDE; Q15628; -.
DR DNASU; 8717; -.
DR Ensembl; ENST00000345057; ENSP00000341268; ENSG00000102871.
DR GeneID; 8717; -.
DR KEGG; hsa:8717; -.
DR UCSC; uc002erh.1; human.
DR CTD; 8717; -.
DR GeneCards; GC16M067188; -.
DR HGNC; HGNC:12030; TRADD.
DR HPA; CAB004602; -.
DR MIM; 603500; gene.
DR neXtProt; NX_Q15628; -.
DR PharmGKB; PA36707; -.
DR eggNOG; NOG47236; -.
DR HOGENOM; HOG000059664; -.
DR HOVERGEN; HBG054083; -.
DR InParanoid; Q15628; -.
DR KO; K03171; -.
DR OMA; LRFCGRQ; -.
DR OrthoDB; EOG7QRQVQ; -.
DR PhylomeDB; Q15628; -.
DR Reactome; REACT_578; Apoptosis.
DR SignaLink; Q15628; -.
DR EvolutionaryTrace; Q15628; -.
DR GeneWiki; TRADD; -.
DR GenomeRNAi; 8717; -.
DR NextBio; 32687; -.
DR PRO; PR:Q15628; -.
DR ArrayExpress; Q15628; -.
DR Bgee; Q15628; -.
DR CleanEx; HS_TRADD; -.
DR Genevestigator; Q15628; -.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0043235; C:receptor complex; IDA:BHF-UCL.
DR GO; GO:0060090; F:binding, bridging; IPI:BHF-UCL.
DR GO; GO:0004871; F:signal transducer activity; IEA:InterPro.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; TAS:BHF-UCL.
DR GO; GO:0051798; P:positive regulation of hair follicle development; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:2001239; P:regulation of extrinsic apoptotic signaling pathway in absence of ligand; TAS:Reactome.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; TAS:BHF-UCL.
DR Gene3D; 1.10.533.10; -; 1.
DR Gene3D; 3.30.70.680; -; 1.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR009095; TRADD_N.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF09034; TRADD_N; 1.
DR ProDom; PD182470; TRADD_N; 1.
DR SMART; SM00005; DEATH; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF55044; SSF55044; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Apoptosis; Complete proteome; Cytoplasm; Cytoskeleton;
KW Nucleus; Reference proteome.
FT CHAIN 1 312 Tumor necrosis factor receptor type 1-
FT associated DEATH domain protein.
FT /FTId=PRO_0000065602.
FT DOMAIN 179 289 Death.
FT REGION 222 289 Interaction with KRT14 and KRT18.
FT MOTIF 147 163 Nuclear export signal (By similarity).
FT MOTIF 231 244 Nuclear localization signal (By
FT similarity).
FT COMPBIAS 192 198 Poly-Pro.
FT STRAND 12 25
FT HELIX 28 33
FT TURN 35 37
FT HELIX 38 52
FT TURN 56 58
FT STRAND 59 66
FT STRAND 68 79
FT HELIX 80 91
FT HELIX 94 106
FT STRAND 114 120
FT HELIX 125 128
FT HELIX 132 141
FT HELIX 150 162
SQ SEQUENCE 312 AA; 34247 MW; 5645D7E63E5FF05A CRC64;
MAAGQNGHEE WVGSAYLFVE SSLDKVVLSD AYAHPQQKVA VYRALQAALA ESGGSPDVLQ
MLKIHRSDPQ LIVQLRFCGR QPCGRFLRAY REGALRAALQ RSLAAALAQH SVPLQLELRA
GAERLDALLA DEERCLSCIL AQQPDRLRDE ELAELEDALR NLKCGSGARG GDGEVASAPL
QPPVPSLSEV KPPPPPPPAQ TFLFQGQPVV NRPLSLKDQQ TFARSVGLKW RKVGRSLQRG
CRALRDPALD SLAYEYEREG LYEQAFQLLR RFVQAEGRRA TLQRLVEALE ENELTSLAED
LLGLTDPNGG LA
//
ID TRADD_HUMAN Reviewed; 312 AA.
AC Q15628; B2RDS3; Q52NZ1;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 15-JUL-1999, sequence version 2.
DT 22-JAN-2014, entry version 135.
DE RecName: Full=Tumor necrosis factor receptor type 1-associated DEATH domain protein;
DE Short=TNFR1-associated DEATH domain protein;
DE AltName: Full=TNFRSF1A-associated via death domain;
GN Name=TRADD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=7758105; DOI=10.1016/0092-8674(95)90070-5;
RA Hsu H., Xiong J., Goeddel D.V.;
RT "The TNF receptor 1-associated protein TRADD signals cell death and
RT NF-kappa B activation.";
RL Cell 81:495-504(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Scheuerpflug C.G., Dechant M., Fellenberg J., Ewerbeck V.,
RA Debatin K.M.;
RT "Sequence, genomic organisation, and mutation analysis of the human
RT TRADD gene in childhood B- and T-lineage acute lymphoblastic leukemia
RT and ALPS.";
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Kaiser C., Kohstall B., Kieser A.;
RT "Cloning of the human TRADD gene locus.";
RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Mammary gland;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Pancreas;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP INTERACTION WITH RIPK1.
RX PubMed=8612133; DOI=10.1016/S1074-7613(00)80252-6;
RA Hsu H., Huang J., Shu H.-B., Baichwal V.R., Goeddel D.V.;
RT "TNF-dependent recruitment of the protein kinase RIP to the TNF
RT receptor-1 signaling complex.";
RL Immunity 4:387-396(1996).
RN [10]
RP INTERACTION WITH SQSTM1.
RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044;
RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.;
RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB
RT activation.";
RL EMBO J. 18:3044-3053(1999).
RN [11]
RP INTERACTION WITH HIPK2.
RX PubMed=11032752; DOI=10.1006/bbrc.2000.3700;
RA Li X., Wang Y., Debatin K.-M., Hug H.;
RT "The serine/threonine kinase HIPK2 interacts with TRADD, but not with
RT CD95 or TNF-R1 in 293T cells.";
RL Biochem. Biophys. Res. Commun. 277:513-517(2000).
RN [12]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH KRT14 AND KRT18.
RX PubMed=11684708; DOI=10.1083/jcb.200103078;
RA Inada H., Izawa I., Nishizawa M., Fujita E., Kiyono T., Takahashi T.,
RA Momoi T., Inagaki M.;
RT "Keratin attenuates tumor necrosis factor-induced cytotoxicity through
RT association with TRADD.";
RL J. Cell Biol. 155:415-426(2001).
RN [13]
RP INTERACTION WITH DAB2IP.
RX PubMed=15310755; DOI=10.1074/jbc.M407617200;
RA Zhang H., Zhang R., Luo Y., D'Alessio A., Pober J.S., Min W.;
RT "AIP1/DAB2IP, a novel member of the Ras-GAP family, transduces TRAF2-
RT induced ASK1-JNK activation.";
RL J. Biol. Chem. 279:44955-44965(2004).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [15]
RP STRUCTURE BY NMR OF 1-179.
RX PubMed=10911999; DOI=10.1016/S1097-2765(00)80270-1;
RA Tsao D.H., McDonagh T., Telliez J.-B., Hsu S., Malakian K., Xu G.Y.,
RA Lin L.L.;
RT "Solution structure of N-TRADD and characterization of the interaction
RT of N-TRADD and C-TRAF2, a key step in the TNFR1 signaling pathway.";
RL Mol. Cell 5:1051-1057(2000).
RN [16]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-179 IN COMPLEX WITH TRAF2.
RX PubMed=10892748; DOI=10.1016/S0092-8674(00)80889-2;
RA Park Y.C., Ye H., Hsia C., Segal D., Rich R.L., Liou H.C.,
RA Myszka D.G., Wu H.;
RT "A novel mechanism of TRAF signaling revealed by structural and
RT functional analyses of the TRADD-TRAF2 interaction.";
RL Cell 101:777-787(2000).
CC -!- FUNCTION: The nuclear form acts as a tumor suppressor by
CC preventing ubiquitination and degradation of isoform p19ARF/ARF of
CC CDKN2A by TRIP12: acts by interacting with TRIP12, leading to
CC disrupt interaction between TRIP12 and isoform p19ARF/ARF of
CC CDKN2A (By similarity). Adapter molecule for TNFRSF1A/TNFR1 that
CC specifically associates with the cytoplasmic domain of activated
CC TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression
CC of TRADD leads to two major TNF-induced responses, apoptosis and
CC activation of NF-kappa-B.
CC -!- SUBUNIT: Interacts with TRIP12 (By similarity). Heterodimer with
CC TNFRSF1A/TNFR1. Interacts with DAB2IP, FADD, HIPK2, KRT14, KRT16,
CC KRT17, KRT18, RIPK1, SQSTM1, TRAF1, TRAF2 and TRPC4AP.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-359215, EBI-359215;
CC P05783:KRT18; NbExp=11; IntAct=EBI-359215, EBI-297888;
CC P19438:TNFRSF1A; NbExp=11; IntAct=EBI-359215, EBI-299451;
CC Q12933:TRAF2; NbExp=2; IntAct=EBI-359215, EBI-355744;
CC -!- SUBCELLULAR LOCATION: Nucleus (By similarity). Cytoplasm (By
CC similarity). Cytoplasm, cytoskeleton. Note=Shuttles between the
CC cytoplasm and the nucleus (By similarity).
CC -!- TISSUE SPECIFICITY: Found in all examined tissues.
CC -!- DOMAIN: Requires the intact death domain to associate with
CC TNFRSF1A/TNFR1.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA98482.1; Type=Erroneous initiation;
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/tradd/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; L41690; AAA98482.1; ALT_INIT; mRNA.
DR EMBL; AJ311614; CAC38018.2; -; Genomic_DNA.
DR EMBL; AJ311615; CAC38018.2; JOINED; Genomic_DNA.
DR EMBL; AJ311616; CAC38018.2; JOINED; Genomic_DNA.
DR EMBL; AY995114; AAX89407.1; -; Genomic_DNA.
DR EMBL; BT006934; AAP35580.1; -; mRNA.
DR EMBL; AY575851; AAS68637.1; -; Genomic_DNA.
DR EMBL; AK315654; BAG38020.1; -; mRNA.
DR EMBL; CH471092; EAW83081.1; -; Genomic_DNA.
DR EMBL; BC004491; AAH04491.1; -; mRNA.
DR PIR; A56911; A56911.
DR RefSeq; NP_003780.1; NM_003789.3.
DR UniGene; Hs.460996; -.
DR PDB; 1F2H; NMR; -; A=1-169.
DR PDB; 1F3V; X-ray; 2.00 A; A=1-179.
DR PDBsum; 1F2H; -.
DR PDBsum; 1F3V; -.
DR ProteinModelPortal; Q15628; -.
DR SMR; Q15628; 1-169.
DR DIP; DIP-285N; -.
DR IntAct; Q15628; 14.
DR MINT; MINT-99115; -.
DR STRING; 9606.ENSP00000341268; -.
DR PhosphoSite; Q15628; -.
DR DMDM; 6094511; -.
DR PaxDb; Q15628; -.
DR PRIDE; Q15628; -.
DR DNASU; 8717; -.
DR Ensembl; ENST00000345057; ENSP00000341268; ENSG00000102871.
DR GeneID; 8717; -.
DR KEGG; hsa:8717; -.
DR UCSC; uc002erh.1; human.
DR CTD; 8717; -.
DR GeneCards; GC16M067188; -.
DR HGNC; HGNC:12030; TRADD.
DR HPA; CAB004602; -.
DR MIM; 603500; gene.
DR neXtProt; NX_Q15628; -.
DR PharmGKB; PA36707; -.
DR eggNOG; NOG47236; -.
DR HOGENOM; HOG000059664; -.
DR HOVERGEN; HBG054083; -.
DR InParanoid; Q15628; -.
DR KO; K03171; -.
DR OMA; LRFCGRQ; -.
DR OrthoDB; EOG7QRQVQ; -.
DR PhylomeDB; Q15628; -.
DR Reactome; REACT_578; Apoptosis.
DR SignaLink; Q15628; -.
DR EvolutionaryTrace; Q15628; -.
DR GeneWiki; TRADD; -.
DR GenomeRNAi; 8717; -.
DR NextBio; 32687; -.
DR PRO; PR:Q15628; -.
DR ArrayExpress; Q15628; -.
DR Bgee; Q15628; -.
DR CleanEx; HS_TRADD; -.
DR Genevestigator; Q15628; -.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR GO; GO:0043235; C:receptor complex; IDA:BHF-UCL.
DR GO; GO:0060090; F:binding, bridging; IPI:BHF-UCL.
DR GO; GO:0004871; F:signal transducer activity; IEA:InterPro.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; TAS:BHF-UCL.
DR GO; GO:0051798; P:positive regulation of hair follicle development; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:2001239; P:regulation of extrinsic apoptotic signaling pathway in absence of ligand; TAS:Reactome.
DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; TAS:BHF-UCL.
DR Gene3D; 1.10.533.10; -; 1.
DR Gene3D; 3.30.70.680; -; 1.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR009095; TRADD_N.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF09034; TRADD_N; 1.
DR ProDom; PD182470; TRADD_N; 1.
DR SMART; SM00005; DEATH; 1.
DR SUPFAM; SSF47986; SSF47986; 1.
DR SUPFAM; SSF55044; SSF55044; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Apoptosis; Complete proteome; Cytoplasm; Cytoskeleton;
KW Nucleus; Reference proteome.
FT CHAIN 1 312 Tumor necrosis factor receptor type 1-
FT associated DEATH domain protein.
FT /FTId=PRO_0000065602.
FT DOMAIN 179 289 Death.
FT REGION 222 289 Interaction with KRT14 and KRT18.
FT MOTIF 147 163 Nuclear export signal (By similarity).
FT MOTIF 231 244 Nuclear localization signal (By
FT similarity).
FT COMPBIAS 192 198 Poly-Pro.
FT STRAND 12 25
FT HELIX 28 33
FT TURN 35 37
FT HELIX 38 52
FT TURN 56 58
FT STRAND 59 66
FT STRAND 68 79
FT HELIX 80 91
FT HELIX 94 106
FT STRAND 114 120
FT HELIX 125 128
FT HELIX 132 141
FT HELIX 150 162
SQ SEQUENCE 312 AA; 34247 MW; 5645D7E63E5FF05A CRC64;
MAAGQNGHEE WVGSAYLFVE SSLDKVVLSD AYAHPQQKVA VYRALQAALA ESGGSPDVLQ
MLKIHRSDPQ LIVQLRFCGR QPCGRFLRAY REGALRAALQ RSLAAALAQH SVPLQLELRA
GAERLDALLA DEERCLSCIL AQQPDRLRDE ELAELEDALR NLKCGSGARG GDGEVASAPL
QPPVPSLSEV KPPPPPPPAQ TFLFQGQPVV NRPLSLKDQQ TFARSVGLKW RKVGRSLQRG
CRALRDPALD SLAYEYEREG LYEQAFQLLR RFVQAEGRRA TLQRLVEALE ENELTSLAED
LLGLTDPNGG LA
//
MIM
603500
*RECORD*
*FIELD* NO
603500
*FIELD* TI
*603500 TUMOR NECROSIS FACTOR RECEPTOR 1-ASSOCIATED DEATH DOMAIN PROTEIN;
TRADD
;;TNFR1-ASSOCIATED DEATH DOMAIN PROTEIN
read more*FIELD* TX
DESCRIPTION
TRADD is a key effector protein in the TNF receptor-1 (TNFR1; 191190)
and death receptor-3 (DR3, or TNFRSF25; 603366) signaling pathways
(Pobezinskaya et al., 2011).
CLONING
Many diverse activities of tumor necrosis factor (TNF) are signaled
through TNF receptor-1 (TNFR1; 191190). TNFR1 contains an intracellular
death domain (see DR3; 603366) that is required for signaling antiviral
activity, programmed cell death, and NF-kappa-B (164011) activation. By
using a yeast 2-hybrid screen to identify proteins that interact with
the death domain of TNFR1, Hsu et al. (1995) isolated cDNAs encoding a
34-kD protein that they designated TRADD (TNFR1-associated death domain
protein). The predicted 312-amino acid TRADD protein contains a
111-amino acid death domain with sequence similarity to that of TNFR1.
Northern blot analysis revealed that the 1.4-kb TRADD mRNA is expressed
ubiquitously.
Pan et al. (1996) isolated the mouse Tradd gene. The predicted mouse and
human TRADD proteins are 75% identical.
GENE FUNCTION
Hsu et al. (1995) found that overexpression of TRADD led to 2 major
TNF-induced responses, apoptosis and activation of NF-kappa-B. They
determined that the death domain of TRADD was capable of mediating TRADD
oligomerization, TNFR1 interaction, stimulation of apoptosis, and
NF-kappa-B activation. TRADD-mediated cell death could be suppressed by
expression of the cowpox virus crmA gene, which encodes an inhibitor of
ICE (147678), a cysteine protease involved in TNF-induced apoptosis.
However, crmA expression did not inhibit NF-kappa-B activation by TRADD,
demonstrating that the 2 signaling pathways emanating from TRADD are
distinct.
By fluorescence microscopy and immunoprecipitation analysis, Wesemann et
al. (2004) found that Ifng (147570) induced an association between the N
terminus of Tradd and Stat1 (600555) in both the nucleus and cytoplasm
of mouse macrophages. Ifng-induced Stat1 activation was enhanced in
cells treated with siRNA to Tradd, suggesting that TRADD is a negative
regulator of Ifng-induced Stat1 DNA binding, activation, and function.
Li et al. (2013) discovered that death domains in several proteins,
including TRADD, FADD (602457), RIPK1 (603453), and TNFR1, were directly
inactivated by NleB, an enteropathogenic E. coli type III secretion
system effector known to inhibit host NF-kappa-B signaling. NleB
contained an unprecedented N-acetylglucosamine (GlcNAc) transferase
activity that specifically modified a conserved arginine in these death
domains (arg235 in the TRADD death domain). NleB GlcNAcylation of death
domains blocked homotypic/heterotypic death domain interactions and
assembly of the oligomeric TNFR1 complex, thereby disrupting TNF
signaling in enteropathogenic E. coli infected cells, including
NF-kappa-B signaling, apoptosis, and necroptosis. Type III-delivered
NleB also blocked FAS ligand (134638) and TRAIL (603598)-induced cell
death by preventing formation of a FADD-mediated death-inducing
signaling complex (DISC). The arginine GlcNAc transferase activity of
NleB was required for bacterial colonization in the mouse model of
enteropathogenic E. coli infection.
Pearson et al. (2013) independently reported that the type III secretion
system (T3SS) effector NleB1 from enteropathogenic E. coli binds to host
cell death-domain-containing proteins and thereby inhibits death
receptor signaling. Protein interaction studies identified FADD, TRADD,
and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or
injected by the bacterial T3SS prevented Fas ligand or TNF-induced
formation of the canonical DISC and proteolytic activation of caspase-8
(601763), an essential step in death receptor-induced apoptosis. This
inhibition depended on the N-acetylglucosamine transferase activity of
NleB1, which specifically modified arg117 in the death domain of FADD.
The importance of the death receptor apoptotic pathway to host defense
was demonstrated using mice deficient in the FAS signaling pathway,
which showed delayed clearance of the enteropathogenic E. coli-like
mouse pathogen Citrobacter rodentium and reversion to virulence of an
NleB mutant. Pearson et al. (2013) concluded that the activity of NleB
suggested that enteropathogenic E. coli and other attaching and effacing
pathogens antagonize death receptor-induced apoptosis of infected cells,
thereby blocking a major antimicrobial host response.
BIOCHEMICAL FEATURES
Park et al. (2000) determined the crystal structure of the complex
between the N-terminal domain of TRADD (residues 1 to 169) and the TRAF
domain of TRAF2 (601895; residues 327 to 501) at 2.0-angstrom
resolution. The structure revealed a novel mode of interaction mediated
by a relatively extensive protein-protein interface.
GENE STRUCTURE
Pan et al. (1996) determined that the mouse Tradd gene contains 4 exons
and spans less than 7 kb.
MAPPING
By analysis of an interspecific backcross, Pan et al. (1996) mapped the
mouse Tradd gene to the distal region of mouse chromosome 8, in a region
showing homology of synteny to human chromosome 16q22. By FISH,
Scheuerpflug et al. (2001) mapped the human TRADD gene to chromosome
16q22.
ANIMAL MODEL
Using T cells from Tradd -/- mice, Pobezinskaya et al. (2011)
demonstrated that the proliferative response of both Cd4 (186940) and
Cd8 (see 186910) T cells to Tl1a (TNFSF15; 604052) was dependent on
Tradd. Stimulation of MAP kinase (see MAPK8; 601158) signaling and
activation of NF-kappa-B in response to Tl1a were also dramatically
reduced in Tradd -/- T cells. Tradd was required for recruitment of Rip1
(RIPK1; 603453) and Traf2 to the Dr3 signaling complex and for
ubiquitination of Rip1. Pobezinskaya et al. (2011) concluded that TRADD
is essential in DR3 signaling.
*FIELD* RF
1. Hsu, H.; Xiong, J.; Goeddel, D. V.: The TNF receptor 1-associated
protein TRADD signals cell death and NF-kappa-B activation. Cell 81:
495-504, 1995.
2. Li, S.; Zhang, L.; Yao, Q.; Li, L.; Dong, N.; Rong, J.; Gao, W.;
Ding, X.; Sun, L.; Chen, X.; Chen, S.; Shao, F.: Pathogen blocks
host death receptor signaling by arginine GlcNAcylation of death domains. Nature 501:
242-246, 2013.
3. Pan, M.-G.; Xiong, J.; Copeland, N. G.; Gilbert, D. J.; Jenkins,
N. A.; Goeddel, D. V.: Sequence, genomic organization, and chromosome
localization of the mouse TRADD gene. J. Inflamm. 46: 168-175, 1996.
4. Park, Y. C.; Ye, H.; Hsia, C.; Segal, D.; Rich, R. L.; Liou, H.-C.;
Myszka, D. G.; Wu, H.: A novel mechanism of TRAF signaling revealed
by structural and functional analyses of the TRADD-TRAF2 interaction. Cell 101:
777-787, 2000.
5. Pearson, J. S.; Giogha, C.; Ong, S. Y.; Kennedy, C. L.; Kelly,
M.; Robinson, K. S.; Lung, T. W. F.; Mansell, A.; Riedmaier, P.; Oates,
C. V. L.; Zaid, A.; Muhlen, S.; and 13 others: A type III effector
antagonizes death receptor signalling during bacterial gut infection. Nature 501:
247-251, 2013.
6. Pobezinskaya, Y. L.; Choksi, S.; Morgan, M. J.; Cao, X.; Liu, Z.
: The adaptor protein TRADD is essential for TNF-like ligand 1A/death
receptor 3 signaling. J. Immun. 186: 5212-5216, 2011.
7. Scheuerpflug, C. G.; Lichter, P.; Debatin, K.-M.; Mincheva, A.
: Assignment of TRADD to human chromosome band 16q22 by in situ hybridization. Cytogenet.
Cell Genet. 92: 347-348, 2001.
8. Wesemann, D. R.; Qin, H.; Kokorina, N.; Benveniste, E. N.: TRADD
interacts with STAT1-alpha and influences interferon-gamma signaling. Nature
Immun. 5: 199-207, 2004. Note: Erratum: Nature Immun. 5: 344 only,
2004.
*FIELD* CN
Ada Hamosh - updated: 12/12/2013
Ada Hamosh - updated: 12/11/2013
Matthew B. Gross - updated: 4/3/2012
Paul J. Converse - updated: 3/22/2012
Paul J. Converse - updated: 4/29/2004
Carol A. Bocchini - updated: 8/8/2001
Stylianos E. Antonarakis - updated: 8/3/2000
*FIELD* CD
Rebekah S. Rasooly: 2/8/1999
*FIELD* ED
alopez: 12/12/2013
alopez: 12/11/2013
mgross: 4/3/2012
terry: 3/22/2012
carol: 7/19/2006
mgross: 11/18/2004
mgross: 4/29/2004
mcapotos: 8/8/2001
mgross: 8/3/2000
alopez: 5/26/1999
alopez: 2/8/1999
*RECORD*
*FIELD* NO
603500
*FIELD* TI
*603500 TUMOR NECROSIS FACTOR RECEPTOR 1-ASSOCIATED DEATH DOMAIN PROTEIN;
TRADD
;;TNFR1-ASSOCIATED DEATH DOMAIN PROTEIN
read more*FIELD* TX
DESCRIPTION
TRADD is a key effector protein in the TNF receptor-1 (TNFR1; 191190)
and death receptor-3 (DR3, or TNFRSF25; 603366) signaling pathways
(Pobezinskaya et al., 2011).
CLONING
Many diverse activities of tumor necrosis factor (TNF) are signaled
through TNF receptor-1 (TNFR1; 191190). TNFR1 contains an intracellular
death domain (see DR3; 603366) that is required for signaling antiviral
activity, programmed cell death, and NF-kappa-B (164011) activation. By
using a yeast 2-hybrid screen to identify proteins that interact with
the death domain of TNFR1, Hsu et al. (1995) isolated cDNAs encoding a
34-kD protein that they designated TRADD (TNFR1-associated death domain
protein). The predicted 312-amino acid TRADD protein contains a
111-amino acid death domain with sequence similarity to that of TNFR1.
Northern blot analysis revealed that the 1.4-kb TRADD mRNA is expressed
ubiquitously.
Pan et al. (1996) isolated the mouse Tradd gene. The predicted mouse and
human TRADD proteins are 75% identical.
GENE FUNCTION
Hsu et al. (1995) found that overexpression of TRADD led to 2 major
TNF-induced responses, apoptosis and activation of NF-kappa-B. They
determined that the death domain of TRADD was capable of mediating TRADD
oligomerization, TNFR1 interaction, stimulation of apoptosis, and
NF-kappa-B activation. TRADD-mediated cell death could be suppressed by
expression of the cowpox virus crmA gene, which encodes an inhibitor of
ICE (147678), a cysteine protease involved in TNF-induced apoptosis.
However, crmA expression did not inhibit NF-kappa-B activation by TRADD,
demonstrating that the 2 signaling pathways emanating from TRADD are
distinct.
By fluorescence microscopy and immunoprecipitation analysis, Wesemann et
al. (2004) found that Ifng (147570) induced an association between the N
terminus of Tradd and Stat1 (600555) in both the nucleus and cytoplasm
of mouse macrophages. Ifng-induced Stat1 activation was enhanced in
cells treated with siRNA to Tradd, suggesting that TRADD is a negative
regulator of Ifng-induced Stat1 DNA binding, activation, and function.
Li et al. (2013) discovered that death domains in several proteins,
including TRADD, FADD (602457), RIPK1 (603453), and TNFR1, were directly
inactivated by NleB, an enteropathogenic E. coli type III secretion
system effector known to inhibit host NF-kappa-B signaling. NleB
contained an unprecedented N-acetylglucosamine (GlcNAc) transferase
activity that specifically modified a conserved arginine in these death
domains (arg235 in the TRADD death domain). NleB GlcNAcylation of death
domains blocked homotypic/heterotypic death domain interactions and
assembly of the oligomeric TNFR1 complex, thereby disrupting TNF
signaling in enteropathogenic E. coli infected cells, including
NF-kappa-B signaling, apoptosis, and necroptosis. Type III-delivered
NleB also blocked FAS ligand (134638) and TRAIL (603598)-induced cell
death by preventing formation of a FADD-mediated death-inducing
signaling complex (DISC). The arginine GlcNAc transferase activity of
NleB was required for bacterial colonization in the mouse model of
enteropathogenic E. coli infection.
Pearson et al. (2013) independently reported that the type III secretion
system (T3SS) effector NleB1 from enteropathogenic E. coli binds to host
cell death-domain-containing proteins and thereby inhibits death
receptor signaling. Protein interaction studies identified FADD, TRADD,
and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or
injected by the bacterial T3SS prevented Fas ligand or TNF-induced
formation of the canonical DISC and proteolytic activation of caspase-8
(601763), an essential step in death receptor-induced apoptosis. This
inhibition depended on the N-acetylglucosamine transferase activity of
NleB1, which specifically modified arg117 in the death domain of FADD.
The importance of the death receptor apoptotic pathway to host defense
was demonstrated using mice deficient in the FAS signaling pathway,
which showed delayed clearance of the enteropathogenic E. coli-like
mouse pathogen Citrobacter rodentium and reversion to virulence of an
NleB mutant. Pearson et al. (2013) concluded that the activity of NleB
suggested that enteropathogenic E. coli and other attaching and effacing
pathogens antagonize death receptor-induced apoptosis of infected cells,
thereby blocking a major antimicrobial host response.
BIOCHEMICAL FEATURES
Park et al. (2000) determined the crystal structure of the complex
between the N-terminal domain of TRADD (residues 1 to 169) and the TRAF
domain of TRAF2 (601895; residues 327 to 501) at 2.0-angstrom
resolution. The structure revealed a novel mode of interaction mediated
by a relatively extensive protein-protein interface.
GENE STRUCTURE
Pan et al. (1996) determined that the mouse Tradd gene contains 4 exons
and spans less than 7 kb.
MAPPING
By analysis of an interspecific backcross, Pan et al. (1996) mapped the
mouse Tradd gene to the distal region of mouse chromosome 8, in a region
showing homology of synteny to human chromosome 16q22. By FISH,
Scheuerpflug et al. (2001) mapped the human TRADD gene to chromosome
16q22.
ANIMAL MODEL
Using T cells from Tradd -/- mice, Pobezinskaya et al. (2011)
demonstrated that the proliferative response of both Cd4 (186940) and
Cd8 (see 186910) T cells to Tl1a (TNFSF15; 604052) was dependent on
Tradd. Stimulation of MAP kinase (see MAPK8; 601158) signaling and
activation of NF-kappa-B in response to Tl1a were also dramatically
reduced in Tradd -/- T cells. Tradd was required for recruitment of Rip1
(RIPK1; 603453) and Traf2 to the Dr3 signaling complex and for
ubiquitination of Rip1. Pobezinskaya et al. (2011) concluded that TRADD
is essential in DR3 signaling.
*FIELD* RF
1. Hsu, H.; Xiong, J.; Goeddel, D. V.: The TNF receptor 1-associated
protein TRADD signals cell death and NF-kappa-B activation. Cell 81:
495-504, 1995.
2. Li, S.; Zhang, L.; Yao, Q.; Li, L.; Dong, N.; Rong, J.; Gao, W.;
Ding, X.; Sun, L.; Chen, X.; Chen, S.; Shao, F.: Pathogen blocks
host death receptor signaling by arginine GlcNAcylation of death domains. Nature 501:
242-246, 2013.
3. Pan, M.-G.; Xiong, J.; Copeland, N. G.; Gilbert, D. J.; Jenkins,
N. A.; Goeddel, D. V.: Sequence, genomic organization, and chromosome
localization of the mouse TRADD gene. J. Inflamm. 46: 168-175, 1996.
4. Park, Y. C.; Ye, H.; Hsia, C.; Segal, D.; Rich, R. L.; Liou, H.-C.;
Myszka, D. G.; Wu, H.: A novel mechanism of TRAF signaling revealed
by structural and functional analyses of the TRADD-TRAF2 interaction. Cell 101:
777-787, 2000.
5. Pearson, J. S.; Giogha, C.; Ong, S. Y.; Kennedy, C. L.; Kelly,
M.; Robinson, K. S.; Lung, T. W. F.; Mansell, A.; Riedmaier, P.; Oates,
C. V. L.; Zaid, A.; Muhlen, S.; and 13 others: A type III effector
antagonizes death receptor signalling during bacterial gut infection. Nature 501:
247-251, 2013.
6. Pobezinskaya, Y. L.; Choksi, S.; Morgan, M. J.; Cao, X.; Liu, Z.
: The adaptor protein TRADD is essential for TNF-like ligand 1A/death
receptor 3 signaling. J. Immun. 186: 5212-5216, 2011.
7. Scheuerpflug, C. G.; Lichter, P.; Debatin, K.-M.; Mincheva, A.
: Assignment of TRADD to human chromosome band 16q22 by in situ hybridization. Cytogenet.
Cell Genet. 92: 347-348, 2001.
8. Wesemann, D. R.; Qin, H.; Kokorina, N.; Benveniste, E. N.: TRADD
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*FIELD* CN
Ada Hamosh - updated: 12/12/2013
Ada Hamosh - updated: 12/11/2013
Matthew B. Gross - updated: 4/3/2012
Paul J. Converse - updated: 3/22/2012
Paul J. Converse - updated: 4/29/2004
Carol A. Bocchini - updated: 8/8/2001
Stylianos E. Antonarakis - updated: 8/3/2000
*FIELD* CD
Rebekah S. Rasooly: 2/8/1999
*FIELD* ED
alopez: 12/12/2013
alopez: 12/11/2013
mgross: 4/3/2012
terry: 3/22/2012
carol: 7/19/2006
mgross: 11/18/2004
mgross: 4/29/2004
mcapotos: 8/8/2001
mgross: 8/3/2000
alopez: 5/26/1999
alopez: 2/8/1999