ID TNFA_HUMAN Reviewed; 233 AA. AC P01375; O43647; Q9P1Q2; Q9UIV3; DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot. DT 21-JUL-1986, sequence version 1. DT 11-DEC-2019, entry version 251. DE RecName: Full=Tumor necrosis factor; DE AltName: Full=Cachectin; DE AltName: Full=TNF-alpha; DE AltName: Full=Tumor necrosis factor ligand superfamily member 2; DE Short=TNF-a; DE Contains: DE RecName: Full=Tumor necrosis factor, membrane form; DE AltName: Full=N-terminal fragment; DE Short=NTF; DE Contains: DE RecName: Full=Intracellular domain 1; DE Short=ICD1; DE Contains: DE RecName: Full=Intracellular domain 2; DE Short=ICD2; DE Contains: DE RecName: Full=C-domain 1; DE Contains: DE RecName: Full=C-domain 2; DE Contains: DE RecName: Full=Tumor necrosis factor, soluble form; DE Flags: Precursor; GN Name=TNF; Synonyms=TNFA, TNFSF2; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=3555974; DOI=10.1101/sqb.1986.051.01.073; RA Nedospasov S.A., Shakhov A.N., Turetskaya R.L., Mett V.A., Azizov M.M., RA Georgiev G.P., Korobko V.G., Dobrynin V.N., Filippov S.A., Bystrov N.S., RA Boldyreva E.F., Chuvpilo S.A., Chumakov A.M., Shingarova L.N., RA Ovchinnikov Y.A.; RT "Tandem arrangement of genes coding for tumor necrosis factor (TNF-alpha) RT and lymphotoxin (TNF-beta) in the human genome."; RL Cold Spring Harb. Symp. Quant. Biol. 51:611-624(1986). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RX PubMed=6392892; DOI=10.1038/312724a0; RA Pennica D., Nedwin G.E., Hayflick J.S., Seeburg P.H., Derynck R., RA Palladino M.A., Kohr W.J., Aggarwal B.B., Goeddel D.V.; RT "Human tumour necrosis factor: precursor structure, expression and homology RT to lymphotoxin."; RL Nature 312:724-729(1984). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RX PubMed=3883195; DOI=10.1038/313803a0; RA Shirai T., Yamaguchi H., Ito H., Todd C.W., Wallace R.B.; RT "Cloning and expression in Escherichia coli of the gene for human tumour RT necrosis factor."; RL Nature 313:803-806(1985). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA]. RX PubMed=2995927; DOI=10.1093/nar/13.17.6361; RA Nedwin G.E., Naylor S.L., Sakaguchi A.Y., Smith D.H., Jarrett-Nedwin J., RA Pennica D., Goeddel D.V., Gray P.W.; RT "Human lymphotoxin and tumor necrosis factor genes: structure, homology and RT chromosomal localization."; RL Nucleic Acids Res. 13:6361-6373(1985). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=3856324; DOI=10.1126/science.3856324; RA Wang A.M., Creasey A.A., Ladner M.B., Lin L.S., Strickler J., RA van Arsdell J.N., Yamamoto R., Mark D.F.; RT "Molecular cloning of the complementary DNA for human tumor necrosis RT factor."; RL Science 228:149-154(1985). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=3932069; DOI=10.1111/j.1432-1033.1985.tb09226.x; RA Marmenout A., Fransen L., Tavernier J., van der Heyden J., Tizard R., RA Kawashima E., Shaw A., Johnson M.J., Semon D., Mueller R., RA Ruysschaert M.-R., van Vliet A., Fiers W.; RT "Molecular cloning and expression of human tumor necrosis factor and RT comparison with mouse tumor necrosis factor."; RL Eur. J. Biochem. 152:515-522(1985). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=8499947; DOI=10.1038/ng0293-137; RA Iris F.J.M., Bougueleret L., Prieur S., Caterina D., Primas G., Perrot V., RA Jurka J., Rodriguez-Tome P., Claverie J.-M., Dausset J., Cohen D.; RT "Dense Alu clustering and a potential new member of the NF kappa B family RT within a 90 kilobase HLA class III segment."; RL Nat. Genet. 3:137-145(1993). RN [8] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10202016; RA Neville M.J., Campbell R.D.; RT "A new member of the Ig superfamily and a V-ATPase G subunit are among the RT predicted products of novel genes close to the TNF locus in the human RT MHC."; RL J. Immunol. 162:4745-4754(1999). RN [9] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14656967; DOI=10.1101/gr.1736803; RA Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., Campbell R.D., RA Hood L.; RT "Analysis of the gene-dense major histocompatibility complex class III RT region and its comparison to mouse."; RL Genome Res. 13:2621-2636(2003). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Shiina S., Tamiya G., Oka A., Inoko H.; RT "Homo sapiens 2,229,817bp genomic DNA of 6p21.3 HLA class I region."; RL Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases. RN [11] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Shiina T., Ota M., Katsuyama Y., Hashimoto N., Inoko H.; RT "Genome diversity in HLA: a new strategy for detection of genetic RT polymorphisms in expressed genes within the HLA class III and class I RT regions."; RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases. RN [12] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG SeattleSNPs variation discovery resource; RL Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases. RN [13] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT LEU-84. RG NIEHS SNPs program; RL Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases. RN [14] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Blood; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [15] RP PROTEIN SEQUENCE OF 77-99, AND GLYCOSYLATION AT SER-80. RX PubMed=8631363; DOI=10.1111/j.1432-1033.1996.00431.x; RA Takakura-Yamamoto R., Yamamoto S., Fukuda S., Kurimoto M.; RT "O-glycosylated species of natural human tumor-necrosis factor-alpha."; RL Eur. J. Biochem. 235:431-437(1996). RN [16] RP NUCLEOTIDE SEQUENCE [MRNA] OF 77-233. RA Jang J.S., Kim B.E.; RL Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases. RN [17] RP NUCLEOTIDE SEQUENCE [MRNA] OF 84-214. RC TISSUE=Prostatic carcinoma; RA Shao C., Yan W., Zhu F., Yue W., Chai Y., Zhao Z., Wang C.; RL Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases. RN [18] RP PHOSPHORYLATION (MEMBRANE FORM). RX PubMed=8597870; RA Pocsik E., Duda E., Wallach D.; RT "Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in RT transfected HeLa cells."; RL J. Inflamm. 45:152-160(1995). RN [19] RP PHOSPHORYLATION BY CK1, AND DEPHOSPHORYLATION. RX PubMed=10205166; DOI=10.1093/emboj/18.8.2119; RA Watts A.D., Hunt N.H., Wanigasekara Y., Bloomfield G., Wallach D., RA Roufogalis B.D., Chaudhri G.; RT "A casein kinase I motif present in the cytoplasmic domain of members of RT the tumour necrosis factor ligand family is implicated in 'reverse RT signalling'."; RL EMBO J. 18:2119-2126(1999). RN [20] RP MUTAGENESIS. RX PubMed=2009860; RA Ostade X.V., Tavernier J., Prange T., Fiers W.; RT "Localization of the active site of human tumour necrosis factor (hTNF) by RT mutational analysis."; RL EMBO J. 10:827-836(1991). RN [21] RP MYRISTOYLATION AT LYS-19 AND LYS-20. RX PubMed=1402651; DOI=10.1084/jem.176.4.1053; RA Stevenson F.T., Bursten S.L., Locksley R.M., Lovett D.H.; RT "Myristyl acylation of the tumor necrosis factor alpha precursor on RT specific lysine residues."; RL J. Exp. Med. 176:1053-1062(1992). RN [22] RP CLEAVAGE BY ADAM17. RX PubMed=9034191; DOI=10.1038/385733a0; RA Moss M.L., Jin S.-L.C., Milla M.E., Burkhart W., Carter H.L., Chen W.-J., RA Clay W.C., Didsbury J.R., Hassler D., Hoffman C.R., Kost T.A., RA Lambert M.H., Leesnitzer M.A., McCauley P., McGeehan G., Mitchell J., RA Moyer M., Pahel G., Rocque W., Overton L.K., Schoenen F., Seaton T., RA Su J.-L., Warner J., Willard D., Becherer J.D.; RT "Cloning of a disintegrin metalloproteinase that processes precursor RT tumour-necrosis factor-alpha."; RL Nature 385:733-736(1997). RN [23] RP POLYMORPHISM, AND INVOLVEMENT IN SUSCEPTIBILITY TO MALARIA. RX PubMed=10369255; DOI=10.1038/9649; RA Knight J.C., Udalova I., Hill A.V., Greenwood B.M., Peshu N., Marsh K., RA Kwiatkowski D.; RT "A polymorphism that affects OCT-1 binding to the TNF promoter region is RT associated with severe malaria."; RL Nat. Genet. 22:145-150(1999). RN [24] RP FUNCTION OF TNF INTRACELLULAR DOMAIN, CLEAVAGE BY SPPL2A AND SPPL2B, AND RP SUBCELLULAR LOCATION. RX PubMed=16829952; DOI=10.1038/ncb1440; RA Friedmann E., Hauben E., Maylandt K., Schleeger S., Vreugde S., RA Lichtenthaler S.F., Kuhn P.H., Stauffer D., Rovelli G., Martoglio B.; RT "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in RT activated dendritic cells to trigger IL-12 production."; RL Nat. Cell Biol. 8:843-848(2006). RN [25] RP CLEAVAGE BY SPPL2A AND SPPL2B, CLEAVAGE SITE, INTERACTION WITH SPPL2B, AND RP IDENTIFICATION BY MASS SPECTROMETRY. RX PubMed=16829951; DOI=10.1038/ncb1450; RA Fluhrer R., Grammer G., Israel L., Condron M.M., Haffner C., Friedmann E., RA Bohland C., Imhof A., Martoglio B., Teplow D.B., Haass C.; RT "A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD RT aspartyl protease SPPL2b."; RL Nat. Cell Biol. 8:894-896(2006). RN [26] RP FUNCTION. RX PubMed=22517918; DOI=10.1189/jlb.1211623; RA Jinesh G.G., Chunduru S., Kamat A.M.; RT "Smac mimetic enables the anticancer action of BCG-stimulated neutrophils RT through TNF-alpha but not through TRAIL and FasL."; RL J. Leukoc. Biol. 92:233-244(2012). RN [27] RP FUNCTION. RX PubMed=23396208; DOI=10.1038/nm.3085; RA Nie H., Zheng Y., Li R., Guo T.B., He D., Fang L., Liu X., Xiao L., RA Chen X., Wan B., Chin Y.E., Zhang J.Z.; RT "Phosphorylation of FOXP3 controls regulatory T cell function and is RT inhibited by TNF-alpha in rheumatoid arthritis."; RL Nat. Med. 19:322-328(2013). RN [28] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS). RX PubMed=2922050; DOI=10.1038/338225a0; RA Jones E.Y., Stuart D.I., Walker N.P.; RT "Structure of tumour necrosis factor."; RL Nature 338:225-228(1989). RN [29] RP X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS). RX PubMed=1964681; RA Jones E.Y., Stuart D.I., Walker N.P.; RT "The structure of tumour necrosis factor -- implications for biological RT function."; RL J. Cell Sci. Suppl. 13:11-18(1990). RN [30] RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS). RX PubMed=2551905; DOI=10.2210/pdb1tnf/pdb; RA Eck M.J., Sprang S.R.; RT "The structure of tumor necrosis factor-alpha at 2.6-A resolution. RT Implications for receptor binding."; RL J. Biol. Chem. 264:17595-17605(1989). RN [31] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF MUTANT ARG-107. RX PubMed=9488135; DOI=10.1093/protein/10.10.1101; RA Reed C., Fu Z.Q., Wu J., Xue Y.N., Harrison R.W., Chen M.J., Weber I.T.; RT "Crystal structure of TNF-alpha mutant R31D with greater affinity for RT receptor R1 compared with R2."; RL Protein Eng. 10:1101-1107(1997). RN [32] RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF MUTANT SER-3. RX PubMed=9442056; DOI=10.1074/jbc.273.4.2153; RA Cha S.S., Kim J.S., Cho H.S., Shin N.K., Jeong W., Shin H.C., Kim Y.J., RA Hahn J.H., Oh B.H.; RT "High resolution crystal structure of a human tumor necrosis factor-alpha RT mutant with low systemic toxicity."; RL J. Biol. Chem. 273:2153-2160(1998). RN [33] RP INVOLVEMENT IN PSORIATIC ARTHRITIS SUSCEPTIBILITY. RX PubMed=12746914; DOI=10.1002/art.10935; RA Balding J., Kane D., Livingstone W., Mynett-Johnson L., Bresnihan B., RA Smith O., FitzGerald O.; RT "Cytokine gene polymorphisms: association with psoriatic arthritis RT susceptibility and severity."; RL Arthritis Rheum. 48:1408-1413(2003). RN [34] RP INVOLVEMENT IN SUSCEPTIBILITY TO HBV INFECTION. RX PubMed=12915457; DOI=10.1093/hmg/ddg262; RA Kim Y.J., Lee H.-S., Yoon J.-H., Kim C.Y., Park M.H., Kim L.H., Park B.L., RA Shin H.D.; RT "Association of TNF-alpha promoter polymorphisms with the clearance of RT hepatitis B virus infection."; RL Hum. Mol. Genet. 12:2541-2546(2003). CC -!- FUNCTION: Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It CC is mainly secreted by macrophages and can induce cell death of certain CC tumor cell lines. It is potent pyrogen causing fever by direct action CC or by stimulation of interleukin-1 secretion and is implicated in the CC induction of cachexia, Under certain conditions it can stimulate cell CC proliferation and induce cell differentiation. Impairs regulatory T- CC cells (Treg) function in individuals with rheumatoid arthritis via CC FOXP3 dephosphorylation. Upregulates the expression of protein CC phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue CC of FOXP3, thereby inactivating FOXP3 and rendering Treg cells CC functionally defective (PubMed:23396208). Key mediator of cell death in CC the anticancer action of BCG-stimulated neutrophils in combination with CC DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line CC (PubMed:22517918, PubMed:16829952, PubMed:23396208). Induces insulin CC resistance in adipocytes via inhibition of insulin-induced IRS1 CC tyrosine phosphorylation and insulin-induced glucose uptake. Induces CC GKAP42 protein degradation in adipocytes which is partially responsible CC for TNF-induced insulin resistance (By similarity). CC {ECO:0000250|UniProtKB:P06804, ECO:0000269|PubMed:16829952, CC ECO:0000269|PubMed:22517918, ECO:0000269|PubMed:23396208}. CC -!- FUNCTION: The TNF intracellular domain (ICD) form induces IL12 CC production in dendritic cells. {ECO:0000269|PubMed:16829952}. CC -!- SUBUNIT: Homotrimer. Interacts with SPPL2B. CC {ECO:0000269|PubMed:16829951}. CC -!- INTERACTION: CC Self; NbExp=3; IntAct=EBI-359977, EBI-359977; CC Q9DHW0:2L (xeno); NbExp=2; IntAct=EBI-359977, EBI-15810797; CC O89110:Casp8 (xeno); NbExp=2; IntAct=EBI-359977, EBI-851690; CC Q8UYL3:crmE (xeno); NbExp=3; IntAct=EBI-359977, EBI-7539950; CC O88351:Ikbkb (xeno); NbExp=3; IntAct=EBI-359977, EBI-447960; CC Q9Y6K9:IKBKG; NbExp=3; IntAct=EBI-359977, EBI-81279; CC Q60855:Ripk1 (xeno); NbExp=3; IntAct=EBI-359977, EBI-529119; CC Q60769:Tnfaip3 (xeno); NbExp=2; IntAct=EBI-359977, EBI-646595; CC P19438:TNFRSF1A; NbExp=15; IntAct=EBI-359977, EBI-299451; CC P25118:Tnfrsf1a (xeno); NbExp=3; IntAct=EBI-359977, EBI-518014; CC P20333:TNFRSF1B; NbExp=2; IntAct=EBI-359977, EBI-358983; CC Q3U0V2:Tradd (xeno); NbExp=2; IntAct=EBI-359977, EBI-1544032; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16829952}; CC Single-pass type II membrane protein {ECO:0000269|PubMed:16829952}. CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, membrane form]: Membrane; CC Single-pass type II membrane protein. CC -!- SUBCELLULAR LOCATION: [Tumor necrosis factor, soluble form]: Secreted. CC -!- SUBCELLULAR LOCATION: [C-domain 1]: Secreted. CC -!- SUBCELLULAR LOCATION: [C-domain 2]: Secreted. CC -!- PTM: The soluble form derives from the membrane form by proteolytic CC processing. The membrane-bound form is further proteolytically CC processed by SPPL2A or SPPL2B through regulated intramembrane CC proteolysis producing TNF intracellular domains (ICD1 and ICD2) CC released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into CC the extracellular space. {ECO:0000269|PubMed:16829951, CC ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:9034191}. CC -!- PTM: The membrane form, but not the soluble form, is phosphorylated on CC serine residues. Dephosphorylation of the membrane form occurs by CC binding to soluble TNFRSF1A/TNFR1. {ECO:0000269|PubMed:10205166, CC ECO:0000269|PubMed:8597870}. CC -!- PTM: O-glycosylated; glycans contain galactose, N-acetylgalactosamine CC and N-acetylneuraminic acid. {ECO:0000269|PubMed:8631363}. CC -!- POLYMORPHISM: Genetic variations in TNF influence susceptibility to CC hepatitis B virus (HBV) infection [MIM:610424]. CC -!- POLYMORPHISM: Genetic variations in TNF are involved in susceptibility CC to malaria [MIM:611162]. CC -!- DISEASE: Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, CC seronegative arthritis associated with psoriasis. It is a heterogeneous CC disorder ranging from a mild, non-destructive disease to a severe, CC progressive, erosive arthropathy. Five types of psoriatic arthritis CC have been defined: asymmetrical oligoarthritis characterized by primary CC involvement of the small joints of the fingers or toes; asymmetrical CC arthritis which involves the joints of the extremities; symmetrical CC polyarthritis characterized by a rheumatoid like pattern that can CC involve hands, wrists, ankles, and feet; arthritis mutilans, which is a CC rare but deforming and destructive condition; arthritis of the CC sacroiliac joints and spine (psoriatic spondylitis). CC {ECO:0000269|PubMed:12746914}. Note=Disease susceptibility is CC associated with variations affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the tumor necrosis factor family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAF71992.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=CAA75070.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=Wikipedia; Note=Tumor necrosis factor alpha entry; CC URL="https://en.wikipedia.org/wiki/Tumor_necrosis_factor-alpha"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/TNFaID319.html"; CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/tnf/"; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/tnf/"; CC -!- WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and CC polymorphism database; CC URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=TNF"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M16441; AAA61200.1; -; Genomic_DNA. DR EMBL; X02910; CAA26669.1; -; Genomic_DNA. DR EMBL; X01394; CAA25650.1; -; mRNA. DR EMBL; M10988; AAA61198.1; -; mRNA. DR EMBL; M26331; AAA36758.1; -; Genomic_DNA. DR EMBL; Z15026; CAA78745.1; -; Genomic_DNA. DR EMBL; Y14768; CAA75070.1; ALT_SEQ; Genomic_DNA. DR EMBL; AF129756; AAD18091.1; -; Genomic_DNA. DR EMBL; BA000025; BAB63396.1; -; Genomic_DNA. DR EMBL; AB088112; BAC54944.1; -; Genomic_DNA. DR EMBL; AY066019; AAL47581.1; -; Genomic_DNA. DR EMBL; AY214167; AAO21132.1; -; Genomic_DNA. DR EMBL; BC028148; AAH28148.1; -; mRNA. DR EMBL; AF043342; AAC03542.1; -; mRNA. DR EMBL; AF098751; AAF71992.1; ALT_FRAME; mRNA. DR CCDS; CCDS4702.1; -. DR PIR; A93585; QWHUN. DR RefSeq; NP_000585.2; NM_000594.3. DR PDB; 1A8M; X-ray; 2.30 A; A/B/C=77-233. DR PDB; 1TNF; X-ray; 2.60 A; A/B/C=77-233. DR PDB; 2AZ5; X-ray; 2.10 A; A/B/C/D=86-233. DR PDB; 2E7A; X-ray; 1.80 A; A/B/C=77-233. DR PDB; 2TUN; X-ray; 3.10 A; A/B/C/D/E/F=77-233. DR PDB; 2ZJC; X-ray; 2.50 A; A/B/C=77-233. DR PDB; 2ZPX; X-ray; 2.83 A; A/B/C=77-233. DR PDB; 3ALQ; X-ray; 3.00 A; A/B/C/D/E/F=77-233. DR PDB; 3IT8; X-ray; 2.80 A; A/B/C/G/H/I=82-233. DR PDB; 3L9J; X-ray; 2.10 A; T=85-233. DR PDB; 3WD5; X-ray; 3.10 A; A=77-233. DR PDB; 4G3Y; X-ray; 2.60 A; C=77-233. DR PDB; 4TSV; X-ray; 1.80 A; A=84-233. DR PDB; 4TWT; X-ray; 2.85 A; A/B/C/D=77-233. DR PDB; 4Y6O; X-ray; 1.60 A; C/D=17-23. DR PDB; 5M2I; X-ray; 2.15 A; A/B/C/D/E/F=77-233. DR PDB; 5M2J; X-ray; 1.90 A; A=77-233. DR PDB; 5M2M; X-ray; 2.30 A; A/B/C/G/I/M=77-233. DR PDB; 5MU8; X-ray; 3.00 A; A/B/C/D/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b/c/d/e=77-233. DR PDB; 5TSW; X-ray; 2.50 A; A/B/C/D/E/F=84-233. DR PDB; 5UUI; X-ray; 1.40 A; A=77-233. DR PDB; 5WUX; X-ray; 2.90 A; E/F/G=77-233. DR PDB; 5YOY; X-ray; 2.73 A; A/B/C/J/K/L=76-233. DR PDBsum; 1A8M; -. DR PDBsum; 1TNF; -. DR PDBsum; 2AZ5; -. DR PDBsum; 2E7A; -. DR PDBsum; 2TUN; -. DR PDBsum; 2ZJC; -. DR PDBsum; 2ZPX; -. DR PDBsum; 3ALQ; -. DR PDBsum; 3IT8; -. DR PDBsum; 3L9J; -. DR PDBsum; 3WD5; -. DR PDBsum; 4G3Y; -. DR PDBsum; 4TSV; -. DR PDBsum; 4TWT; -. DR PDBsum; 4Y6O; -. DR PDBsum; 5M2I; -. DR PDBsum; 5M2J; -. DR PDBsum; 5M2M; -. DR PDBsum; 5MU8; -. DR PDBsum; 5TSW; -. DR PDBsum; 5UUI; -. DR PDBsum; 5WUX; -. DR PDBsum; 5YOY; -. DR SMR; P01375; -. DR BioGrid; 112979; 270. DR CORUM; P01375; -. DR DIP; DIP-2895N; -. DR IntAct; P01375; 110. DR MINT; P01375; -. DR STRING; 9606.ENSP00000398698; -. DR BindingDB; P01375; -. DR ChEMBL; CHEMBL1825; -. DR DrugBank; DB00051; Adalimumab. DR DrugBank; DB04956; Afelimomab. DR DrugBank; DB05879; AME-527. DR DrugBank; DB01427; Amrinone. DR DrugBank; DB05767; Andrographolide. DR DrugBank; DB05676; Apremilast. DR DrugBank; DB05513; Atiprimod. DR DrugBank; DB11967; Binimetinib. DR DrugBank; DB08904; Certolizumab pegol. DR DrugBank; DB00608; Chloroquine. DR DrugBank; DB01407; Clenbuterol. DR DrugBank; DB05744; CRx-139. DR DrugBank; DB05758; CYT007-TNFQb. DR DrugBank; DB06444; Dexanabinol. DR DrugBank; DB12140; Dilmapimod. DR DrugBank; DB00668; Epinephrine. DR DrugBank; DB00005; Etanercept. DR DrugBank; DB05869; Ethyl pyruvate. DR DrugBank; DB10770; Foreskin fibroblast (neonatal). DR DrugBank; DB10772; Foreskin keratinocyte (neonatal). DR DrugBank; DB01296; Glucosamine. DR DrugBank; DB13751; Glycyrrhizic acid. DR DrugBank; DB06674; Golimumab. DR DrugBank; DB00065; Infliximab. DR DrugBank; DB02325; Isopropyl alcohol. DR DrugBank; DB05303; OMS-103HP. DR DrugBank; DB06495; Onercept. DR DrugBank; DB05992; Plinabulin. DR DrugBank; DB05218; PN0621. DR DrugBank; DB09221; Polaprezinc. DR DrugBank; DB08910; Pomalidomide. DR DrugBank; DB05968; PR-104. DR DrugBank; DB01411; Pranlukast. DR DrugBank; DB00852; Pseudoephedrine. DR DrugBank; DB05207; SD118. DR DrugBank; DB05412; Talmapimod. DR DrugBank; DB01041; Thalidomide. DR DrugBank; DB05470; VX-702. DR DrugBank; DB05017; YSIL6. DR DrugCentral; P01375; -. DR GlyConnect; 609; -. DR iPTMnet; P01375; -. DR PhosphoSitePlus; P01375; -. DR SwissPalm; P01375; -. DR UniCarbKB; P01375; -. DR BioMuta; TNF; -. DR DMDM; 135934; -. DR MassIVE; P01375; -. DR PaxDb; P01375; -. DR PeptideAtlas; P01375; -. DR PRIDE; P01375; -. DR ProteomicsDB; 12707; -. DR ProteomicsDB; 51379; -. DR ABCD; P01375; -. DR DNASU; 7124; -. DR Ensembl; ENST00000376122; ENSP00000365290; ENSG00000204490. DR Ensembl; ENST00000383496; ENSP00000372988; ENSG00000206439. DR Ensembl; ENST00000412275; ENSP00000392858; ENSG00000228321. DR Ensembl; ENST00000420425; ENSP00000410668; ENSG00000228849. DR Ensembl; ENST00000443707; ENSP00000389492; ENSG00000230108. DR Ensembl; ENST00000448781; ENSP00000389490; ENSG00000223952. DR Ensembl; ENST00000449264; ENSP00000398698; ENSG00000232810. DR GeneID; 7124; -. DR KEGG; hsa:7124; -. DR CTD; 7124; -. DR DisGeNET; 7124; -. DR EuPathDB; HostDB:ENSG00000232810.3; -. DR GeneCards; TNF; -. DR HGNC; HGNC:11892; TNF. DR MalaCards; TNF; -. DR MIM; 191160; gene. DR MIM; 607507; phenotype. DR MIM; 610424; phenotype. DR MIM; 611162; phenotype. DR neXtProt; NX_P01375; -. DR OpenTargets; ENSG00000232810; -. DR Orphanet; 40050; NON RARE IN EUROPE: Psoriatic arthritis. DR PharmGKB; PA435; -. DR eggNOG; ENOG410ISAN; Eukaryota. DR eggNOG; ENOG410YQC4; LUCA. DR GeneTree; ENSGT00970000193380; -. DR HOGENOM; HOG000048729; -. DR InParanoid; P01375; -. DR KO; K03156; -. DR OMA; SPCHRET; -. DR OrthoDB; 1124938at2759; -. DR PhylomeDB; P01375; -. DR TreeFam; TF332169; -. DR Reactome; R-HSA-381340; Transcriptional regulation of white adipocyte differentiation. DR Reactome; R-HSA-5357786; TNFR1-induced proapoptotic signaling. DR Reactome; R-HSA-5357905; Regulation of TNFR1 signaling. DR Reactome; R-HSA-5357956; TNFR1-induced NFkappaB signaling pathway. DR Reactome; R-HSA-5626978; TNFR1-mediated ceramide production. DR Reactome; R-HSA-5668541; TNFR2 non-canonical NF-kB pathway. DR Reactome; R-HSA-6783783; Interleukin-10 signaling. DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling. DR Reactome; R-HSA-75893; TNF signaling. DR SIGNOR; P01375; -. DR ChiTaRS; TNF; human. DR EvolutionaryTrace; P01375; -. DR GeneWiki; Tumor_necrosis_factor-alpha; -. DR GenomeRNAi; 7124; -. DR Pharos; P01375; Tclin. DR PRO; PR:P01375; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; P01375; protein. DR Bgee; ENSG00000232810; Expressed in 89 organ(s), highest expression level in leukocyte. DR ExpressionAtlas; P01375; baseline and differential. DR Genevisible; P01375; HS. DR GO; GO:0009986; C:cell surface; IDA:BHF-UCL. DR GO; GO:0009897; C:external side of plasma membrane; ISS:BHF-UCL. DR GO; GO:0005576; C:extracellular region; TAS:ARUK-UCL. DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL. DR GO; GO:0005887; C:integral component of plasma membrane; IDA:BHF-UCL. DR GO; GO:0016020; C:membrane; TAS:ARUK-UCL. DR GO; GO:0045121; C:membrane raft; IDA:BHF-UCL. DR GO; GO:0001891; C:phagocytic cup; ISS:BHF-UCL. DR GO; GO:0005886; C:plasma membrane; TAS:Reactome. DR GO; GO:0032991; C:protein-containing complex; TAS:ARUK-UCL. DR GO; GO:0055037; C:recycling endosome; ISS:BHF-UCL. DR GO; GO:0005125; F:cytokine activity; IDA:BHF-UCL. DR GO; GO:0042802; F:identical protein binding; IDA:BHF-UCL. DR GO; GO:0002020; F:protease binding; IPI:BHF-UCL. DR GO; GO:0044212; F:transcription regulatory region DNA binding; IDA:UniProtKB. DR GO; GO:0005164; F:tumor necrosis factor receptor binding; IDA:BHF-UCL. DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB. DR GO; GO:0000187; P:activation of MAPK activity; IDA:BHF-UCL. DR GO; GO:0000185; P:activation of MAPKKK activity; IDA:BHF-UCL. DR GO; GO:0048143; P:astrocyte activation; NAS:ARUK-UCL. DR GO; GO:0071230; P:cellular response to amino acid stimulus; IEA:Ensembl. DR GO; GO:0071316; P:cellular response to nicotine; IDA:UniProtKB. DR GO; GO:0071407; P:cellular response to organic cyclic compound; IDA:UniProtKB. DR GO; GO:0002439; P:chronic inflammatory response to antigenic stimulus; IMP:BHF-UCL. DR GO; GO:0050890; P:cognition; TAS:ARUK-UCL. DR GO; GO:0030866; P:cortical actin cytoskeleton organization; IDA:UniProtKB. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; TAS:Reactome. DR GO; GO:0071550; P:death-inducing signaling complex assembly; TAS:Reactome. DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEA:Ensembl. DR GO; GO:0048566; P:embryonic digestive tract development; IEP:DFLAT. DR GO; GO:0072577; P:endothelial cell apoptotic process; IEA:Ensembl. DR GO; GO:0060664; P:epithelial cell proliferation involved in salivary gland morphogenesis; IEA:Ensembl. DR GO; GO:0030198; P:extracellular matrix organization; IEA:Ensembl. DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:UniProtKB. DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IDA:UniProtKB. DR GO; GO:0006006; P:glucose metabolic process; IEA:Ensembl. DR GO; GO:0006959; P:humoral immune response; IEA:Ensembl. DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB signaling; TAS:Reactome. DR GO; GO:0006954; P:inflammatory response; IDA:UniProtKB. DR GO; GO:0008630; P:intrinsic apoptotic signaling pathway in response to DNA damage; IEA:Ensembl. DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl. DR GO; GO:0050901; P:leukocyte tethering or rolling; IDA:BHF-UCL. DR GO; GO:0031663; P:lipopolysaccharide-mediated signaling pathway; IDA:UniProtKB. DR GO; GO:0000165; P:MAPK cascade; IMP:UniProtKB. DR GO; GO:0001774; P:microglial cell activation; ISS:ARUK-UCL. DR GO; GO:0097527; P:necroptotic signaling pathway; IDA:UniProtKB. DR GO; GO:0010693; P:negative regulation of alkaline phosphatase activity; IEA:Ensembl. DR GO; GO:1900222; P:negative regulation of amyloid-beta clearance; ISS:ARUK-UCL. DR GO; GO:1903347; P:negative regulation of bicellular tight junction assembly; IDA:UniProtKB. DR GO; GO:0061048; P:negative regulation of branching involved in lung morphogenesis; IDA:UniProtKB. DR GO; GO:0002740; P:negative regulation of cytokine secretion involved in immune response; IDA:BHF-UCL. DR GO; GO:0001937; P:negative regulation of endothelial cell proliferation; IEA:Ensembl. DR GO; GO:2001240; P:negative regulation of extrinsic apoptotic signaling pathway in absence of ligand; IDA:BHF-UCL. DR GO; GO:0045599; P:negative regulation of fat cell differentiation; NAS:BHF-UCL. DR GO; GO:0010629; P:negative regulation of gene expression; IDA:UniProtKB. DR GO; GO:0046325; P:negative regulation of glucose import; IEA:Ensembl. DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IDA:BHF-UCL. DR GO; GO:0050995; P:negative regulation of lipid catabolic process; IDA:BHF-UCL. DR GO; GO:0010888; P:negative regulation of lipid storage; NAS:BHF-UCL. DR GO; GO:0045930; P:negative regulation of mitotic cell cycle; IEA:Ensembl. DR GO; GO:0045662; P:negative regulation of myoblast differentiation; IEA:Ensembl. DR GO; GO:0035509; P:negative regulation of myosin-light-chain-phosphatase activity; IDA:UniProtKB. DR GO; GO:0050768; P:negative regulation of neurogenesis; TAS:ARUK-UCL. DR GO; GO:0045668; P:negative regulation of osteoblast differentiation; IEA:Ensembl. DR GO; GO:0043242; P:negative regulation of protein complex disassembly; IDA:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB. DR GO; GO:0045071; P:negative regulation of viral genome replication; IDA:BHF-UCL. DR GO; GO:0030316; P:osteoclast differentiation; IEA:Ensembl. DR GO; GO:1902004; P:positive regulation of amyloid-beta formation; ISS:ARUK-UCL. DR GO; GO:0043065; P:positive regulation of apoptotic process; IDA:UniProtKB. DR GO; GO:2000334; P:positive regulation of blood microparticle formation; IDA:BHF-UCL. DR GO; GO:0060559; P:positive regulation of calcidiol 1-monooxygenase activity; IDA:BHF-UCL. DR GO; GO:0070886; P:positive regulation of calcineurin-NFAT signaling cascade; IDA:MGI. DR GO; GO:0045785; P:positive regulation of cell adhesion; IMP:UniProtKB. DR GO; GO:2000304; P:positive regulation of ceramide biosynthetic process; TAS:Reactome. DR GO; GO:2000343; P:positive regulation of chemokine (C-X-C motif) ligand 2 production; IDA:BHF-UCL. DR GO; GO:0045080; P:positive regulation of chemokine biosynthetic process; IDA:BHF-UCL. DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL. DR GO; GO:0090197; P:positive regulation of chemokine secretion; ISS:ARUK-UCL. DR GO; GO:0002876; P:positive regulation of chronic inflammatory response to antigenic stimulus; IEA:Ensembl. DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IDA:UniProtKB. DR GO; GO:0001819; P:positive regulation of cytokine production; IDA:BHF-UCL. DR GO; GO:0050715; P:positive regulation of cytokine secretion; IDA:BHF-UCL. DR GO; GO:0051091; P:positive regulation of DNA-binding transcription factor activity; IDA:BHF-UCL. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; NAS:BHF-UCL. DR GO; GO:0031622; P:positive regulation of fever generation; ISS:BHF-UCL. DR GO; GO:0050754; P:positive regulation of fractalkine biosynthetic process; ISS:ARUK-UCL. DR GO; GO:0010628; P:positive regulation of gene expression; IDA:UniProtKB. DR GO; GO:0060252; P:positive regulation of glial cell proliferation; IDA:ARUK-UCL. DR GO; GO:0051798; P:positive regulation of hair follicle development; IEA:Ensembl. DR GO; GO:0034116; P:positive regulation of heterotypic cell-cell adhesion; IDA:BHF-UCL. DR GO; GO:0002925; P:positive regulation of humoral immune response mediated by circulating immunoglobulin; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB signaling; IDA:BHF-UCL. DR GO; GO:0050729; P:positive regulation of inflammatory response; TAS:ARUK-UCL. DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IEA:Ensembl. DR GO; GO:0045410; P:positive regulation of interleukin-6 biosynthetic process; ISS:ARUK-UCL. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:ARUK-UCL. DR GO; GO:2000778; P:positive regulation of interleukin-6 secretion; ISS:ARUK-UCL. DR GO; GO:0045416; P:positive regulation of interleukin-8 biosynthetic process; IDA:BHF-UCL. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IMP:UniProtKB. DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:UniProtKB. DR GO; GO:1904999; P:positive regulation of leukocyte adhesion to arterial endothelial cell; IDA:BHF-UCL. DR GO; GO:1904996; P:positive regulation of leukocyte adhesion to vascular endothelial cell; IDA:BHF-UCL. DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IDA:UniProtKB. DR GO; GO:0051044; P:positive regulation of membrane protein ectodomain proteolysis; IDA:BHF-UCL. DR GO; GO:0071677; P:positive regulation of mononuclear cell migration; NAS:BHF-UCL. DR GO; GO:0150078; P:positive regulation of neuroinflammatory response; TAS:ARUK-UCL. DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; ISS:ARUK-UCL. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB. DR GO; GO:1901224; P:positive regulation of NIK/NF-kappaB signaling; IDA:UniProtKB. DR GO; GO:0045429; P:positive regulation of nitric oxide biosynthetic process; IDA:BHF-UCL. DR GO; GO:0051000; P:positive regulation of nitric-oxide synthase activity; IC:ARUK-UCL. DR GO; GO:0051173; P:positive regulation of nitrogen compound metabolic process; ISS:ARUK-UCL. DR GO; GO:0045672; P:positive regulation of osteoclast differentiation; IDA:BHF-UCL. DR GO; GO:0033138; P:positive regulation of peptidyl-serine phosphorylation; IDA:BHF-UCL. DR GO; GO:0050766; P:positive regulation of phagocytosis; IMP:AgBase. DR GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; ISS:ARUK-UCL. DR GO; GO:0071803; P:positive regulation of podosome assembly; IDA:BHF-UCL. DR GO; GO:0043068; P:positive regulation of programmed cell death; IDA:UniProtKB. DR GO; GO:0045732; P:positive regulation of protein catabolic process; IDA:AgBase. DR GO; GO:0031334; P:positive regulation of protein complex assembly; IDA:BHF-UCL. DR GO; GO:0043243; P:positive regulation of protein complex disassembly; IDA:UniProtKB. DR GO; GO:0045860; P:positive regulation of protein kinase activity; IDA:AgBase. DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; ISS:ARUK-UCL. DR GO; GO:2000010; P:positive regulation of protein localization to cell surface; IDA:BHF-UCL. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISS:ARUK-UCL. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IDA:UniProtKB. DR GO; GO:0051222; P:positive regulation of protein transport; IDA:BHF-UCL. DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; ISS:ARUK-UCL. DR GO; GO:0048661; P:positive regulation of smooth muscle cell proliferation; IDA:BHF-UCL. DR GO; GO:1901671; P:positive regulation of superoxide dismutase activity; IDA:BHF-UCL. DR GO; GO:0050806; P:positive regulation of synaptic transmission; ISS:ARUK-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB. DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IDA:UniProtKB. DR GO; GO:0045994; P:positive regulation of translational initiation by iron; IEA:Ensembl. DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; ISS:ARUK-UCL. DR GO; GO:1904707; P:positive regulation of vascular smooth muscle cell proliferation; IEA:Ensembl. DR GO; GO:0060557; P:positive regulation of vitamin D biosynthetic process; IDA:BHF-UCL. DR GO; GO:0043491; P:protein kinase B signaling; IMP:UniProtKB. DR GO; GO:0072659; P:protein localization to plasma membrane; IDA:UniProtKB. DR GO; GO:0032800; P:receptor biosynthetic process; IDA:BHF-UCL. DR GO; GO:0060693; P:regulation of branching involved in salivary gland morphogenesis; IEA:Ensembl. DR GO; GO:2000351; P:regulation of endothelial cell apoptotic process; IMP:ARUK-UCL. DR GO; GO:1903140; P:regulation of establishment of endothelial barrier; IDA:UniProtKB. DR GO; GO:0045598; P:regulation of fat cell differentiation; ISS:ARUK-UCL. DR GO; GO:0043122; P:regulation of I-kappaB kinase/NF-kappaB signaling; IDA:BHF-UCL. DR GO; GO:0051023; P:regulation of immunoglobulin secretion; IEA:Ensembl. DR GO; GO:0050796; P:regulation of insulin secretion; IDA:BHF-UCL. DR GO; GO:0050807; P:regulation of synapse organization; ISS:ARUK-UCL. DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; TAS:ARUK-UCL. DR GO; GO:0006357; P:regulation of transcription by RNA polymerase II; ISS:ARUK-UCL. DR GO; GO:0010803; P:regulation of tumor necrosis factor-mediated signaling pathway; TAS:Reactome. DR GO; GO:0051384; P:response to glucocorticoid; IDA:BHF-UCL. DR GO; GO:0009651; P:response to salt stress; TAS:BHF-UCL. DR GO; GO:0009615; P:response to virus; IDA:BHF-UCL. DR GO; GO:0030730; P:sequestering of triglyceride; IDA:BHF-UCL. DR GO; GO:0033209; P:tumor necrosis factor-mediated signaling pathway; IMP:BHF-UCL. DR CDD; cd00184; TNF; 1. DR Gene3D; 2.60.120.40; -; 1. DR InterPro; IPR006053; TNF. DR InterPro; IPR002959; TNF_alpha. DR InterPro; IPR021184; TNF_CS. DR InterPro; IPR006052; TNF_dom. DR InterPro; IPR008983; Tumour_necrosis_fac-like_dom. DR PANTHER; PTHR11471:SF23; PTHR11471:SF23; 1. DR Pfam; PF00229; TNF; 1. DR PRINTS; PR01234; TNECROSISFCT. DR PRINTS; PR01235; TNFALPHA. DR SMART; SM00207; TNF; 1. DR SUPFAM; SSF49842; SSF49842; 1. DR PROSITE; PS00251; TNF_1; 1. DR PROSITE; PS50049; TNF_2; 1. PE 1: Evidence at protein level; KW 3D-structure; Cell membrane; Cytokine; Direct protein sequencing; KW Disulfide bond; Glycoprotein; Lipoprotein; Membrane; Myristate; KW Phosphoprotein; Polymorphism; Reference proteome; Secreted; Signal-anchor; KW Transmembrane; Transmembrane helix. FT CHAIN 1..233 FT /note="Tumor necrosis factor, membrane form" FT /id="PRO_0000034423" FT CHAIN 1..39 FT /note="Intracellular domain 1" FT /id="PRO_0000417231" FT CHAIN 1..35 FT /note="Intracellular domain 2" FT /id="PRO_0000417232" FT CHAIN 50..? FT /note="C-domain 1" FT /id="PRO_0000417233" FT CHAIN 52..? FT /note="C-domain 2" FT /id="PRO_0000417234" FT CHAIN 77..233 FT /note="Tumor necrosis factor, soluble form" FT /evidence="ECO:0000269|PubMed:3856324" FT /id="PRO_0000034424" FT TOPO_DOM 1..35 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT TRANSMEM 36..56 FT /note="Helical; Signal-anchor for type II membrane protein" FT /evidence="ECO:0000255" FT TOPO_DOM 57..233 FT /note="Extracellular" FT /evidence="ECO:0000255" FT SITE 35..36 FT /note="Cleavage; by SPPL2A or SPPL2B" FT SITE 39..40 FT /note="Cleavage; by SPPL2A or SPPL2B" FT SITE 49..50 FT /note="Cleavage; by SPPL2A or SPPL2B" FT SITE 51..52 FT /note="Cleavage; by SPPL2A or SPPL2B" FT SITE 76..77 FT /note="Cleavage; by ADAM17" FT MOD_RES 2 FT /note="Phosphoserine; by CK1" FT /evidence="ECO:0000305" FT LIPID 19 FT /note="N6-myristoyl lysine" FT /evidence="ECO:0000269|PubMed:1402651" FT LIPID 20 FT /note="N6-myristoyl lysine" FT /evidence="ECO:0000269|PubMed:1402651" FT CARBOHYD 80 FT /note="O-linked (GalNAc...) serine; in soluble form" FT /evidence="ECO:0000269|PubMed:8631363" FT DISULFID 145..177 FT VARIANT 84 FT /note="P -> L (in dbSNP:rs4645843)" FT /evidence="ECO:0000269|Ref.13" FT /id="VAR_019378" FT VARIANT 94 FT /note="A -> T (in dbSNP:rs1800620)" FT /id="VAR_011927" FT MUTAGEN 105 FT /note="L->S: Low activity." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 108 FT /note="R->W: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 112 FT /note="L->F: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 160 FT /note="A->V: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 162 FT /note="S->F: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 167 FT /note="V->A,D: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT MUTAGEN 222 FT /note="E->K: Biologically inactive." FT /evidence="ECO:0000269|PubMed:2009860" FT CONFLICT 63 FT /note="F -> S (in Ref. 5; AAA61198)" FT /evidence="ECO:0000305" FT CONFLICT 84..86 FT /note="PSD -> VNR (in Ref. 17; AAF71992)" FT /evidence="ECO:0000305" FT CONFLICT 183 FT /note="E -> R (in Ref. 16; AAC03542)" FT /evidence="ECO:0000305" FT STRAND 89..94 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 96..98 FT /evidence="ECO:0000244|PDB:5M2I" FT STRAND 99..101 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 104..106 FT /evidence="ECO:0000244|PDB:2ZJC" FT STRAND 108..110 FT /evidence="ECO:0000244|PDB:5M2J" FT STRAND 112..114 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 118..120 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 123..125 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 128..143 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 146..148 FT /evidence="ECO:0000244|PDB:2ZPX" FT STRAND 152..159 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 161..163 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 166..174 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 177..179 FT /evidence="ECO:0000244|PDB:1A8M" FT STRAND 182..185 FT /evidence="ECO:0000244|PDB:4TSV" FT STRAND 189..202 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 207..213 FT /evidence="ECO:0000244|PDB:5UUI" FT HELIX 215..217 FT /evidence="ECO:0000244|PDB:5UUI" FT STRAND 221..223 FT /evidence="ECO:0000244|PDB:3IT8" FT STRAND 225..232 FT /evidence="ECO:0000244|PDB:5UUI" SQ SEQUENCE 233 AA; 25644 MW; 3DF90F96C9031FFE CRC64; MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL LHFGVIGPQR EEFPRDLSLI SPLAQAVRSS SRTPSDKPVA HVVANPQAEG QLQWLNRRAN ALLANGVELR DNQLVVPSEG LYLIYSQVLF KGQGCPSTHV LLTHTISRIA VSYQTKVNLL SAIKSPCQRE TPEGAEAKPW YEPIYLGGVF QLEKGDRLSA EINRPDYLDF AESGQVYFGI IAL //