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P01375

- TNFA_HUMAN

UniProt

P01375 - TNFA_HUMAN

Protein

Tumor necrosis factor

Gene

TNF

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 197 (01 Oct 2014)
      Sequence version 1 (21 Jul 1986)
      Previous versions | rss
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    Functioni

    Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.1 Publication
    The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sitei35 – 362Cleavage; by SPPL2A or SPPL2B
    Sitei39 – 402Cleavage; by SPPL2A or SPPL2B
    Sitei49 – 502Cleavage; by SPPL2A or SPPL2B
    Sitei51 – 522Cleavage; by SPPL2A or SPPL2B
    Sitei76 – 772Cleavage; by ADAM17

    GO - Molecular functioni

    1. cytokine activity Source: BHF-UCL
    2. identical protein binding Source: BHF-UCL
    3. protease binding Source: BHF-UCL
    4. protein binding Source: UniProtKB
    5. transcription regulatory region DNA binding Source: UniProtKB
    6. tumor necrosis factor receptor binding Source: BHF-UCL

    GO - Biological processi

    1. activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
    2. activation of MAPK activity Source: BHF-UCL
    3. activation of MAPKKK activity Source: BHF-UCL
    4. apoptotic process Source: Reactome
    5. apoptotic signaling pathway Source: Reactome
    6. calcium-mediated signaling Source: Ensembl
    7. cell activation Source: Ensembl
    8. cellular amino acid biosynthetic process Source: Ensembl
    9. cellular response to amino acid stimulus Source: Ensembl
    10. cellular response to nicotine Source: UniProtKB
    11. cellular response to organic cyclic compound Source: UniProtKB
    12. chronic inflammatory response to antigenic stimulus Source: BHF-UCL
    13. defense response to Gram-positive bacterium Source: Ensembl
    14. embryonic digestive tract development Source: DFLAT
    15. epithelial cell proliferation involved in salivary gland morphogenesis Source: Ensembl
    16. extracellular matrix organization Source: Ensembl
    17. extrinsic apoptotic signaling pathway Source: UniProtKB
    18. extrinsic apoptotic signaling pathway via death domain receptors Source: UniProtKB
    19. glucose metabolic process Source: Ensembl
    20. humoral immune response Source: Ensembl
    21. inflammatory response Source: UniProtKB
    22. intrinsic apoptotic signaling pathway in response to DNA damage Source: Ensembl
    23. JNK cascade Source: Ensembl
    24. leukocyte tethering or rolling Source: BHF-UCL
    25. lipopolysaccharide-mediated signaling pathway Source: UniProtKB
    26. MAPK cascade Source: UniProtKB
    27. necroptotic signaling pathway Source: UniProtKB
    28. negative regulation of alkaline phosphatase activity Source: Ensembl
    29. negative regulation of branching involved in lung morphogenesis Source: UniProtKB
    30. negative regulation of cell proliferation Source: Ensembl
    31. negative regulation of cytokine secretion involved in immune response Source: BHF-UCL
    32. negative regulation of extrinsic apoptotic signaling pathway in absence of ligand Source: BHF-UCL
    33. negative regulation of fat cell differentiation Source: BHF-UCL
    34. negative regulation of gene expression Source: UniProtKB
    35. negative regulation of glucose import Source: Ensembl
    36. negative regulation of growth of symbiont in host Source: Ensembl
    37. negative regulation of interleukin-6 production Source: BHF-UCL
    38. negative regulation of L-glutamate transport Source: Ensembl
    39. negative regulation of lipid catabolic process Source: BHF-UCL
    40. negative regulation of lipid storage Source: BHF-UCL
    41. negative regulation of osteoblast differentiation Source: Ensembl
    42. negative regulation of protein complex disassembly Source: UniProtKB
    43. negative regulation of transcription, DNA-templated Source: UniProtKB
    44. negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    45. negative regulation of viral genome replication Source: BHF-UCL
    46. organ morphogenesis Source: Ensembl
    47. osteoclast differentiation Source: Ensembl
    48. positive regulation of apoptotic process Source: UniProtKB
    49. positive regulation of calcidiol 1-monooxygenase activity Source: BHF-UCL
    50. positive regulation of chemokine (C-X-C motif) ligand 2 production Source: BHF-UCL
    51. positive regulation of chemokine biosynthetic process Source: BHF-UCL
    52. positive regulation of chemokine production Source: BHF-UCL
    53. positive regulation of chronic inflammatory response to antigenic stimulus Source: Ensembl
    54. positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
    55. positive regulation of cytokine production Source: BHF-UCL
    56. positive regulation of cytokine secretion Source: BHF-UCL
    57. positive regulation of ERK1 and ERK2 cascade Source: BHF-UCL
    58. positive regulation of extrinsic apoptotic signaling pathway via death domain receptors Source: Ensembl
    59. positive regulation of fever generation Source: BHF-UCL
    60. positive regulation of gene expression Source: AgBase
    61. positive regulation of hair follicle development Source: Ensembl
    62. positive regulation of heterotypic cell-cell adhesion Source: BHF-UCL
    63. positive regulation of humoral immune response mediated by circulating immunoglobulin Source: Ensembl
    64. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: BHF-UCL
    65. positive regulation of interferon-gamma production Source: Ensembl
    66. positive regulation of interleukin-18 production Source: Ensembl
    67. positive regulation of interleukin-6 production Source: Ensembl
    68. positive regulation of interleukin-8 biosynthetic process Source: BHF-UCL
    69. positive regulation of JNK cascade Source: Ensembl
    70. positive regulation of JUN kinase activity Source: UniProtKB
    71. positive regulation of MAP kinase activity Source: UniProtKB
    72. positive regulation of membrane protein ectodomain proteolysis Source: BHF-UCL
    73. positive regulation of mitosis Source: Ensembl
    74. positive regulation of mononuclear cell migration Source: BHF-UCL
    75. positive regulation of neuron apoptotic process Source: Ensembl
    76. positive regulation of NFAT protein import into nucleus Source: MGI
    77. positive regulation of NF-kappaB import into nucleus Source: BHF-UCL
    78. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
    79. positive regulation of nitric oxide biosynthetic process Source: BHF-UCL
    80. positive regulation of osteoclast differentiation Source: BHF-UCL
    81. positive regulation of peptidyl-serine phosphorylation Source: BHF-UCL
    82. positive regulation of podosome assembly Source: BHF-UCL
    83. positive regulation of programmed cell death Source: UniProtKB
    84. positive regulation of protein complex assembly Source: BHF-UCL
    85. positive regulation of protein complex disassembly Source: UniProtKB
    86. positive regulation of protein kinase B signaling Source: Ensembl
    87. positive regulation of protein localization to cell surface Source: BHF-UCL
    88. positive regulation of protein phosphorylation Source: UniProtKB
    89. positive regulation of protein transport Source: BHF-UCL
    90. positive regulation of sequence-specific DNA binding transcription factor activity Source: BHF-UCL
    91. positive regulation of smooth muscle cell proliferation Source: BHF-UCL
    92. positive regulation of synaptic transmission Source: Ensembl
    93. positive regulation of transcription, DNA-templated Source: UniProtKB
    94. positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
    95. positive regulation of translational initiation by iron Source: Ensembl
    96. positive regulation of vitamin D biosynthetic process Source: BHF-UCL
    97. protein import into nucleus, translocation Source: UniProtKB
    98. protein kinase B signaling Source: UniProtKB
    99. receptor biosynthetic process Source: BHF-UCL
    100. regulation of branching involved in salivary gland morphogenesis Source: Ensembl
    101. regulation of I-kappaB kinase/NF-kappaB signaling Source: BHF-UCL
    102. regulation of immunoglobulin secretion Source: Ensembl
    103. regulation of insulin secretion Source: BHF-UCL
    104. response to activity Source: Ensembl
    105. response to drug Source: Ensembl
    106. response to glucocorticoid Source: BHF-UCL
    107. response to hypoxia Source: Ensembl
    108. response to mechanical stimulus Source: Ensembl
    109. response to salt stress Source: BHF-UCL
    110. response to virus Source: BHF-UCL
    111. sequestering of triglyceride Source: BHF-UCL
    112. skeletal muscle contraction Source: Ensembl
    113. transformed cell apoptotic process Source: BHF-UCL
    114. tumor necrosis factor-mediated signaling pathway Source: BHF-UCL

    Keywords - Molecular functioni

    Cytokine

    Enzyme and pathway databases

    ReactomeiREACT_1432. TNF signaling.
    REACT_27161. Transcriptional regulation of white adipocyte differentiation.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Tumor necrosis factor
    Alternative name(s):
    Cachectin
    TNF-alpha
    Tumor necrosis factor ligand superfamily member 2
    Short name:
    TNF-a
    Cleaved into the following 6 chains:
    Gene namesi
    Name:TNF
    Synonyms:TNFA, TNFSF2
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    ProteomesiUP000005640: Chromosome 6

    Organism-specific databases

    HGNCiHGNC:11892. TNF.

    Subcellular locationi

    Cell membrane 1 Publication; Single-pass type II membrane protein 1 Publication

    GO - Cellular componenti

    1. cell surface Source: BHF-UCL
    2. external side of plasma membrane Source: BHF-UCL
    3. extracellular region Source: Reactome
    4. extracellular space Source: BHF-UCL
    5. integral component of plasma membrane Source: BHF-UCL
    6. membrane raft Source: BHF-UCL
    7. phagocytic cup Source: BHF-UCL
    8. plasma membrane Source: Reactome
    9. recycling endosome Source: BHF-UCL

    Keywords - Cellular componenti

    Cell membrane, Membrane, Secreted

    Pathology & Biotechi

    Involvement in diseasei

    Psoriatic arthritis (PSORAS) [MIM:607507]: An inflammatory, seronegative arthritis associated with psoriasis. It is a heterogeneous disorder ranging from a mild, non-destructive disease to a severe, progressive, erosive arthropathy. Five types of psoriatic arthritis have been defined: asymmetrical oligoarthritis characterized by primary involvement of the small joints of the fingers or toes; asymmetrical arthritis which involves the joints of the extremities; symmetrical polyarthritis characterized by a rheumatoid like pattern that can involve hands, wrists, ankles, and feet; arthritis mutilans, which is a rare but deforming and destructive condition; arthritis of the sacroiliac joints and spine (psoriatic spondylitis).1 Publication
    Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi105 – 1051L → S: Low activity. 1 Publication
    Mutagenesisi108 – 1081R → W: Biologically inactive. 1 Publication
    Mutagenesisi112 – 1121L → F: Biologically inactive. 1 Publication
    Mutagenesisi160 – 1601A → V: Biologically inactive. 1 Publication
    Mutagenesisi162 – 1621S → F: Biologically inactive. 1 Publication
    Mutagenesisi167 – 1671V → A or D: Biologically inactive. 1 Publication
    Mutagenesisi222 – 2221E → K: Biologically inactive. 1 Publication

    Organism-specific databases

    MIMi607507. phenotype.
    610424. phenotype.
    611162. phenotype.
    Orphaneti40050. Adult psoriatic arthritis.
    PharmGKBiPA435.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Chaini1 – 233233Tumor necrosis factor, membrane formPRO_0000034423Add
    BLAST
    Chaini1 – 3939Intracellular domain 1PRO_0000417231Add
    BLAST
    Chaini1 – 3535Intracellular domain 2PRO_0000417232Add
    BLAST
    Chaini50 – ?C-domain 1PRO_0000417233
    Chaini52 – ?C-domain 2PRO_0000417234
    Chaini77 – 233157Tumor necrosis factor, soluble form1 PublicationPRO_0000034424Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21Phosphoserine; by CK1Curated
    Lipidationi19 – 191N6-myristoyl lysine1 Publication
    Lipidationi20 – 201N6-myristoyl lysine1 Publication
    Glycosylationi80 – 801O-linked (GalNAc...); in soluble form1 Publication
    Disulfide bondi145 ↔ 177

    Post-translational modificationi

    The soluble form derives from the membrane form by proteolytic processing. The membrane-bound form is further proteolytically processed by SPPL2A or SPPL2B through regulated intramembrane proteolysis producing TNF intracellular domains (ICD1 and ICD2) released in the cytosol and TNF C-domain 1 and C-domain 2 secreted into the extracellular space.3 Publications
    The membrane form, but not the soluble form, is phosphorylated on serine residues. Dephosphorylation of the membrane form occurs by binding to soluble TNFRSF1A/TNFR1.2 Publications
    O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid.1 Publication

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Lipoprotein, Myristate, Phosphoprotein

    Proteomic databases

    PaxDbiP01375.
    PRIDEiP01375.

    PTM databases

    PhosphoSiteiP01375.
    UniCarbKBiP01375.

    Miscellaneous databases

    PMAP-CutDBP01375.

    Expressioni

    Gene expression databases

    ArrayExpressiP01375.
    BgeeiP01375.
    CleanExiHS_TNF.
    GenevestigatoriP01375.

    Interactioni

    Subunit structurei

    Homotrimer. Interacts with SPPL2B.1 Publication

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    crmEQ8UYL33EBI-359977,EBI-7539950From a different organism.
    IKBKGQ9Y6K92EBI-359977,EBI-81279
    TNFRSF1AP194389EBI-359977,EBI-299451
    TNFRSF1BP203332EBI-359977,EBI-358983

    Protein-protein interaction databases

    BioGridi112979. 47 interactions.
    DIPiDIP-2895N.
    IntActiP01375. 30 interactions.
    MINTiMINT-1131842.
    STRINGi9606.ENSP00000392858.

    Structurei

    Secondary structure

    1
    233
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Beta strandi89 – 946
    Beta strandi96 – 983
    Beta strandi99 – 1013
    Beta strandi106 – 1083
    Beta strandi112 – 1143
    Beta strandi118 – 1203
    Beta strandi123 – 1253
    Beta strandi130 – 14415
    Beta strandi146 – 1483
    Beta strandi152 – 1598
    Helixi161 – 1633
    Beta strandi167 – 1748
    Beta strandi177 – 1793
    Beta strandi182 – 1854
    Beta strandi189 – 20214
    Beta strandi207 – 2137
    Helixi215 – 2173
    Beta strandi221 – 2233
    Beta strandi225 – 2328

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    1A8MX-ray2.30A/B/C77-233[»]
    1TNFX-ray2.60A/B/C77-233[»]
    2AZ5X-ray2.10A/B/C/D86-233[»]
    2E7AX-ray1.80A/B/C77-233[»]
    2TUNX-ray3.10A/B/C/D/E/F77-233[»]
    2ZJCX-ray2.50A/B/C77-233[»]
    2ZPXX-ray2.83A/B/C77-233[»]
    3ALQX-ray3.00A/B/C/D/E/F77-233[»]
    3IT8X-ray2.80A/B/C/G/H/I82-233[»]
    3L9JX-ray2.10T85-233[»]
    3WD5X-ray3.10A77-233[»]
    4G3YX-ray2.60C77-233[»]
    4TSVX-ray1.80A84-233[»]
    5TSWX-ray2.50A/B/C/D/E/F84-233[»]
    ProteinModelPortaliP01375.
    SMRiP01375. Positions 85-233.
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP01375.

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini1 – 3535CytoplasmicSequence AnalysisAdd
    BLAST
    Topological domaini57 – 233177ExtracellularSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei36 – 5621Helical; Signal-anchor for type II membrane proteinSequence AnalysisAdd
    BLAST

    Family & Domainsi

    Sequence similaritiesi

    Belongs to the tumor necrosis factor family.Curated

    Keywords - Domaini

    Signal-anchor, Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiNOG40413.
    HOGENOMiHOG000048729.
    HOVERGENiHBG012516.
    InParanoidiP01375.
    KOiK03156.
    OMAiPWYEPIY.
    OrthoDBiEOG7V4B0Q.
    PhylomeDBiP01375.
    TreeFamiTF332169.

    Family and domain databases

    Gene3Di2.60.120.40. 1 hit.
    InterProiIPR006053. TNF.
    IPR002959. TNF_alpha.
    IPR021184. TNF_CS.
    IPR006052. TNF_dom.
    IPR008983. Tumour_necrosis_fac-like_dom.
    [Graphical view]
    PfamiPF00229. TNF. 1 hit.
    [Graphical view]
    PRINTSiPR01234. TNECROSISFCT.
    PR01235. TNFALPHA.
    SMARTiSM00207. TNF. 1 hit.
    [Graphical view]
    SUPFAMiSSF49842. SSF49842. 1 hit.
    PROSITEiPS00251. TNF_1. 1 hit.
    PS50049. TNF_2. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P01375-1 [UniParc]FASTAAdd to Basket

    « Hide

    MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL    50
    LHFGVIGPQR EEFPRDLSLI SPLAQAVRSS SRTPSDKPVA HVVANPQAEG 100
    QLQWLNRRAN ALLANGVELR DNQLVVPSEG LYLIYSQVLF KGQGCPSTHV 150
    LLTHTISRIA VSYQTKVNLL SAIKSPCQRE TPEGAEAKPW YEPIYLGGVF 200
    QLEKGDRLSA EINRPDYLDF AESGQVYFGI IAL 233
    Length:233
    Mass (Da):25,644
    Last modified:July 21, 1986 - v1
    Checksum:i3DF90F96C9031FFE
    GO

    Sequence cautioni

    The sequence AAF71992.1 differs from that shown. Reason: Frameshift at positions 91 and 157.
    The sequence CAA75070.1 differs from that shown. Reason: Erroneous gene model prediction.

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti63 – 631F → S in AAA61198. (PubMed:3856324)Curated
    Sequence conflicti84 – 863PSD → VNR in AAF71992. 1 PublicationCurated
    Sequence conflicti183 – 1831E → R in AAC03542. 1 PublicationCurated

    Polymorphismi

    Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIMi:610424].
    Genetic variations in TNF are involved in susceptibility to malaria [MIMi:611162].

    Natural variant

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Natural varianti84 – 841P → L.1 Publication
    Corresponds to variant rs4645843 [ dbSNP | Ensembl ].
    VAR_019378
    Natural varianti94 – 941A → T.
    Corresponds to variant rs1800620 [ dbSNP | Ensembl ].
    VAR_011927

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M16441 Genomic DNA. Translation: AAA61200.1.
    X02910 Genomic DNA. Translation: CAA26669.1.
    X01394 mRNA. Translation: CAA25650.1.
    M10988 mRNA. Translation: AAA61198.1.
    M26331 Genomic DNA. Translation: AAA36758.1.
    Z15026 Genomic DNA. Translation: CAA78745.1.
    Y14768 Genomic DNA. Translation: CAA75070.1. Sequence problems.
    AF129756 Genomic DNA. Translation: AAD18091.1.
    BA000025 Genomic DNA. Translation: BAB63396.1.
    AB088112 Genomic DNA. Translation: BAC54944.1.
    AY066019 Genomic DNA. Translation: AAL47581.1.
    AY214167 Genomic DNA. Translation: AAO21132.1.
    BC028148 mRNA. Translation: AAH28148.1.
    AF043342 mRNA. Translation: AAC03542.1.
    AF098751 mRNA. Translation: AAF71992.1. Frameshift.
    CCDSiCCDS4702.1.
    PIRiA93585. QWHUN.
    RefSeqiNP_000585.2. NM_000594.3.
    UniGeneiHs.241570.

    Genome annotation databases

    EnsembliENST00000376122; ENSP00000365290; ENSG00000204490.
    ENST00000383496; ENSP00000372988; ENSG00000206439.
    ENST00000412275; ENSP00000392858; ENSG00000228321.
    ENST00000420425; ENSP00000410668; ENSG00000228849.
    ENST00000443707; ENSP00000389492; ENSG00000230108.
    ENST00000448781; ENSP00000389490; ENSG00000223952.
    ENST00000449264; ENSP00000398698; ENSG00000232810.
    GeneIDi7124.
    KEGGihsa:7124.
    UCSCiuc003nui.4. human.

    Polymorphism databases

    DMDMi135934.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Web resourcesi

    Wikipedia

    Tumor necrosis factor alpha entry

    Atlas of Genetics and Cytogenetics in Oncology and Haematology
    NIEHS-SNPs
    SeattleSNPs
    SHMPD

    The Singapore human mutation and polymorphism database

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    M16441 Genomic DNA. Translation: AAA61200.1 .
    X02910 Genomic DNA. Translation: CAA26669.1 .
    X01394 mRNA. Translation: CAA25650.1 .
    M10988 mRNA. Translation: AAA61198.1 .
    M26331 Genomic DNA. Translation: AAA36758.1 .
    Z15026 Genomic DNA. Translation: CAA78745.1 .
    Y14768 Genomic DNA. Translation: CAA75070.1 . Sequence problems.
    AF129756 Genomic DNA. Translation: AAD18091.1 .
    BA000025 Genomic DNA. Translation: BAB63396.1 .
    AB088112 Genomic DNA. Translation: BAC54944.1 .
    AY066019 Genomic DNA. Translation: AAL47581.1 .
    AY214167 Genomic DNA. Translation: AAO21132.1 .
    BC028148 mRNA. Translation: AAH28148.1 .
    AF043342 mRNA. Translation: AAC03542.1 .
    AF098751 mRNA. Translation: AAF71992.1 . Frameshift.
    CCDSi CCDS4702.1.
    PIRi A93585. QWHUN.
    RefSeqi NP_000585.2. NM_000594.3.
    UniGenei Hs.241570.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    1A8M X-ray 2.30 A/B/C 77-233 [» ]
    1TNF X-ray 2.60 A/B/C 77-233 [» ]
    2AZ5 X-ray 2.10 A/B/C/D 86-233 [» ]
    2E7A X-ray 1.80 A/B/C 77-233 [» ]
    2TUN X-ray 3.10 A/B/C/D/E/F 77-233 [» ]
    2ZJC X-ray 2.50 A/B/C 77-233 [» ]
    2ZPX X-ray 2.83 A/B/C 77-233 [» ]
    3ALQ X-ray 3.00 A/B/C/D/E/F 77-233 [» ]
    3IT8 X-ray 2.80 A/B/C/G/H/I 82-233 [» ]
    3L9J X-ray 2.10 T 85-233 [» ]
    3WD5 X-ray 3.10 A 77-233 [» ]
    4G3Y X-ray 2.60 C 77-233 [» ]
    4TSV X-ray 1.80 A 84-233 [» ]
    5TSW X-ray 2.50 A/B/C/D/E/F 84-233 [» ]
    ProteinModelPortali P01375.
    SMRi P01375. Positions 85-233.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    BioGridi 112979. 47 interactions.
    DIPi DIP-2895N.
    IntActi P01375. 30 interactions.
    MINTi MINT-1131842.
    STRINGi 9606.ENSP00000392858.

    Chemistry

    BindingDBi P01375.
    ChEMBLi CHEMBL1825.
    DrugBanki DB00051. Adalimumab.
    DB00640. Adenosine.
    DB01427. Amrinone.
    DB01076. Atorvastatin.
    DB00608. Chloroquine.
    DB01407. Clenbuterol.
    DB00005. Etanercept.
    DB01296. Glucosamine.
    DB00065. Infliximab.
    DB00704. Naltrexone.
    DB01411. Pranlukast.
    DB01366. Procaterol.
    DB01232. Saquinavir.
    DB00641. Simvastatin.
    DB01041. Thalidomide.
    GuidetoPHARMACOLOGYi 2635.

    PTM databases

    PhosphoSitei P01375.
    UniCarbKBi P01375.

    Polymorphism databases

    DMDMi 135934.

    Proteomic databases

    PaxDbi P01375.
    PRIDEi P01375.

    Protocols and materials databases

    DNASUi 7124.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000376122 ; ENSP00000365290 ; ENSG00000204490 .
    ENST00000383496 ; ENSP00000372988 ; ENSG00000206439 .
    ENST00000412275 ; ENSP00000392858 ; ENSG00000228321 .
    ENST00000420425 ; ENSP00000410668 ; ENSG00000228849 .
    ENST00000443707 ; ENSP00000389492 ; ENSG00000230108 .
    ENST00000448781 ; ENSP00000389490 ; ENSG00000223952 .
    ENST00000449264 ; ENSP00000398698 ; ENSG00000232810 .
    GeneIDi 7124.
    KEGGi hsa:7124.
    UCSCi uc003nui.4. human.

    Organism-specific databases

    CTDi 7124.
    GeneCardsi GC06P031543.
    GC06Pj31530.
    GC06Pk31525.
    GC06Pl31582.
    GC06Pm31619.
    GC06Pn31533.
    GC06Po31533.
    H-InvDB HIX0165948.
    HGNCi HGNC:11892. TNF.
    MIMi 191160. gene.
    607507. phenotype.
    610424. phenotype.
    611162. phenotype.
    neXtProti NX_P01375.
    Orphaneti 40050. Adult psoriatic arthritis.
    PharmGKBi PA435.
    GenAtlasi Search...

    Phylogenomic databases

    eggNOGi NOG40413.
    HOGENOMi HOG000048729.
    HOVERGENi HBG012516.
    InParanoidi P01375.
    KOi K03156.
    OMAi PWYEPIY.
    OrthoDBi EOG7V4B0Q.
    PhylomeDBi P01375.
    TreeFami TF332169.

    Enzyme and pathway databases

    Reactomei REACT_1432. TNF signaling.
    REACT_27161. Transcriptional regulation of white adipocyte differentiation.

    Miscellaneous databases

    ChiTaRSi TNF. human.
    EvolutionaryTracei P01375.
    GeneWikii Tumor_necrosis_factor-alpha.
    GenomeRNAii 7124.
    NextBioi 27879.
    PMAP-CutDB P01375.
    PROi P01375.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi P01375.
    Bgeei P01375.
    CleanExi HS_TNF.
    Genevestigatori P01375.

    Family and domain databases

    Gene3Di 2.60.120.40. 1 hit.
    InterProi IPR006053. TNF.
    IPR002959. TNF_alpha.
    IPR021184. TNF_CS.
    IPR006052. TNF_dom.
    IPR008983. Tumour_necrosis_fac-like_dom.
    [Graphical view ]
    Pfami PF00229. TNF. 1 hit.
    [Graphical view ]
    PRINTSi PR01234. TNECROSISFCT.
    PR01235. TNFALPHA.
    SMARTi SM00207. TNF. 1 hit.
    [Graphical view ]
    SUPFAMi SSF49842. SSF49842. 1 hit.
    PROSITEi PS00251. TNF_1. 1 hit.
    PS50049. TNF_2. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Tandem arrangement of genes coding for tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) in the human genome."
      Nedospasov S.A., Shakhov A.N., Turetskaya R.L., Mett V.A., Azizov M.M., Georgiev G.P., Korobko V.G., Dobrynin V.N., Filippov S.A., Bystrov N.S., Boldyreva E.F., Chuvpilo S.A., Chumakov A.M., Shingarova L.N., Ovchinnikov Y.A.
      Cold Spring Harb. Symp. Quant. Biol. 51:611-624(1986) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    2. "Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin."
      Pennica D., Nedwin G.E., Hayflick J.S., Seeburg P.H., Derynck R., Palladino M.A., Kohr W.J., Aggarwal B.B., Goeddel D.V.
      Nature 312:724-729(1984) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
    3. "Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor."
      Shirai T., Yamaguchi H., Ito H., Todd C.W., Wallace R.B.
      Nature 313:803-806(1985) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
    4. "Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization."
      Nedwin G.E., Naylor S.L., Sakaguchi A.Y., Smith D.H., Jarrett-Nedwin J., Pennica D., Goeddel D.V., Gray P.W.
      Nucleic Acids Res. 13:6361-6373(1985) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
    5. "Molecular cloning of the complementary DNA for human tumor necrosis factor."
      Wang A.M., Creasey A.A., Ladner M.B., Lin L.S., Strickler J., van Arsdell J.N., Yamamoto R., Mark D.F.
      Science 228:149-154(1985) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
    6. "Molecular cloning and expression of human tumor necrosis factor and comparison with mouse tumor necrosis factor."
      Marmenout A., Fransen L., Tavernier J., van der Heyden J., Tizard R., Kawashima E., Shaw A., Johnson M.J., Semon D., Mueller R., Ruysschaert M.-R., van Vliet A., Fiers W.
      Eur. J. Biochem. 152:515-522(1985) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    7. "Dense Alu clustering and a potential new member of the NF kappa B family within a 90 kilobase HLA class III segment."
      Iris F.J.M., Bougueleret L., Prieur S., Caterina D., Primas G., Perrot V., Jurka J., Rodriguez-Tome P., Claverie J.-M., Dausset J., Cohen D.
      Nat. Genet. 3:137-145(1993) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    8. "A new member of the Ig superfamily and a V-ATPase G subunit are among the predicted products of novel genes close to the TNF locus in the human MHC."
      Neville M.J., Campbell R.D.
      J. Immunol. 162:4745-4754(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    9. "Analysis of the gene-dense major histocompatibility complex class III region and its comparison to mouse."
      Xie T., Rowen L., Aguado B., Ahearn M.E., Madan A., Qin S., Campbell R.D., Hood L.
      Genome Res. 13:2621-2636(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    10. "Homo sapiens 2,229,817bp genomic DNA of 6p21.3 HLA class I region."
      Shiina S., Tamiya G., Oka A., Inoko H.
      Submitted (SEP-1999) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    11. "Genome diversity in HLA: a new strategy for detection of genetic polymorphisms in expressed genes within the HLA class III and class I regions."
      Shiina T., Ota M., Katsuyama Y., Hashimoto N., Inoko H.
      Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
    12. SeattleSNPs variation discovery resource
      Submitted (DEC-2001) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
    13. NIEHS SNPs program
      Submitted (JAN-2003) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT LEU-84.
    14. "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] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Blood.
    15. "O-glycosylated species of natural human tumor-necrosis factor-alpha."
      Takakura-Yamamoto R., Yamamoto S., Fukuda S., Kurimoto M.
      Eur. J. Biochem. 235:431-437(1996) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF 77-99, GLYCOSYLATION AT SER-80.
    16. Jang J.S., Kim B.E.
      Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 77-233.
    17. Shao C., Yan W., Zhu F., Yue W., Chai Y., Zhao Z., Wang C.
      Submitted (MAR-2000) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 84-214.
      Tissue: Prostatic carcinoma.
    18. "Phosphorylation of the 26 kDa TNF precursor in monocytic cells and in transfected HeLa cells."
      Pocsik E., Duda E., Wallach D.
      J. Inflamm. 45:152-160(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION (MEMBRANE FORM).
    19. "A casein kinase I motif present in the cytoplasmic domain of members of the tumour necrosis factor ligand family is implicated in 'reverse signalling'."
      Watts A.D., Hunt N.H., Wanigasekara Y., Bloomfield G., Wallach D., Roufogalis B.D., Chaudhri G.
      EMBO J. 18:2119-2126(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: PHOSPHORYLATION BY CK1, DEPHOSPHORYLATION.
    20. "Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis."
      Ostade X.V., Tavernier J., Prange T., Fiers W.
      EMBO J. 10:827-836(1991) [PubMed] [Europe PMC] [Abstract]
      Cited for: MUTAGENESIS.
    21. "Myristyl acylation of the tumor necrosis factor alpha precursor on specific lysine residues."
      Stevenson F.T., Bursten S.L., Locksley R.M., Lovett D.H.
      J. Exp. Med. 176:1053-1062(1992) [PubMed] [Europe PMC] [Abstract]
      Cited for: MYRISTOYLATION AT LYS-19 AND LYS-20.
    22. Cited for: CLEAVAGE BY ADAM17.
    23. "A polymorphism that affects OCT-1 binding to the TNF promoter region is associated with severe malaria."
      Knight J.C., Udalova I., Hill A.V., Greenwood B.M., Peshu N., Marsh K., Kwiatkowski D.
      Nat. Genet. 22:145-150(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: POLYMORPHISM, INVOLVEMENT IN SUSCEPTIBILITY TO MALARIA.
    24. "SPPL2a and SPPL2b promote intramembrane proteolysis of TNFalpha in activated dendritic cells to trigger IL-12 production."
      Friedmann E., Hauben E., Maylandt K., Schleeger S., Vreugde S., Lichtenthaler S.F., Kuhn P.H., Stauffer D., Rovelli G., Martoglio B.
      Nat. Cell Biol. 8:843-848(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION OF TNF INTRACELLULAR DOMAIN, CLEAVAGE BY SPPL2A AND SPPL2B, SUBCELLULAR LOCATION.
    25. "A gamma-secretase-like intramembrane cleavage of TNFalpha by the GxGD aspartyl protease SPPL2b."
      Fluhrer R., Grammer G., Israel L., Condron M.M., Haffner C., Friedmann E., Bohland C., Imhof A., Martoglio B., Teplow D.B., Haass C.
      Nat. Cell Biol. 8:894-896(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: CLEAVAGE BY SPPL2A AND SPPL2B, CLEAVAGE SITE, INTERACTION WITH SPPL2B, IDENTIFICATION BY MASS SPECTROMETRY.
    26. Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
    27. "The structure of tumour necrosis factor -- implications for biological function."
      Jones E.Y., Stuart D.I., Walker N.P.
      J. Cell Sci. Suppl. 13:11-18(1990) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
    28. "The structure of tumor necrosis factor-alpha at 2.6-A resolution. Implications for receptor binding."
      Eck M.J., Sprang S.R.
      J. Biol. Chem. 264:17595-17605(1989) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
    29. "Crystal structure of TNF-alpha mutant R31D with greater affinity for receptor R1 compared with R2."
      Reed C., Fu Z.Q., Wu J., Xue Y.N., Harrison R.W., Chen M.J., Weber I.T.
      Protein Eng. 10:1101-1107(1997) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF MUTANT ARG-107.
    30. "High resolution crystal structure of a human tumor necrosis factor-alpha mutant with low systemic toxicity."
      Cha S.S., Kim J.S., Cho H.S., Shin N.K., Jeong W., Shin H.C., Kim Y.J., Hahn J.H., Oh B.H.
      J. Biol. Chem. 273:2153-2160(1998) [PubMed] [Europe PMC] [Abstract]
      Cited for: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF MUTANT SER-3.
    31. "Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity."
      Balding J., Kane D., Livingstone W., Mynett-Johnson L., Bresnihan B., Smith O., FitzGerald O.
      Arthritis Rheum. 48:1408-1413(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INVOLVEMENT IN PSORIATIC ARTHRITIS SUSCEPTIBILITY.
    32. "Association of TNF-alpha promoter polymorphisms with the clearance of hepatitis B virus infection."
      Kim Y.J., Lee H.-S., Yoon J.-H., Kim C.Y., Park M.H., Kim L.H., Park B.L., Shin H.D.
      Hum. Mol. Genet. 12:2541-2546(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: INVOLVEMENT IN SUSCEPTIBILITY TO HBV INFECTION.

    Entry informationi

    Entry nameiTNFA_HUMAN
    AccessioniPrimary (citable) accession number: P01375
    Secondary accession number(s): O43647, Q9P1Q2, Q9UIV3
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 21, 1986
    Last sequence update: July 21, 1986
    Last modified: October 1, 2014
    This is version 197 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. Human chromosome 6
      Human chromosome 6: entries, gene names and cross-references to MIM
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3