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Protein

Tumor necrosis factor

Gene

TNF

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

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. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Upregulates the expression of protein phosphatase 1 (PP1), which dephosphorylates the key 'Ser-418' residue of FOXP3, thereby inactivating FOXP3 and rendering Treg cells functionally defective (PubMed:23396208).2 Publications
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

  • cytokine activity Source: BHF-UCL
  • identical protein binding Source: BHF-UCL
  • protease binding Source: BHF-UCL
  • transcription regulatory region DNA binding Source: UniProtKB
  • tumor necrosis factor receptor binding Source: BHF-UCL

GO - Biological processi

  • activation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • activation of MAPK activity Source: BHF-UCL
  • activation of MAPKKK activity Source: BHF-UCL
  • calcium-mediated signaling Source: Ensembl
  • cell activation Source: Ensembl
  • cell surface receptor signaling pathway Source: Reactome
  • cellular response to amino acid stimulus Source: Ensembl
  • cellular response to nicotine Source: UniProtKB
  • cellular response to organic cyclic compound Source: UniProtKB
  • chronic inflammatory response to antigenic stimulus Source: BHF-UCL
  • death-inducing signaling complex assembly Source: Reactome
  • defense response to Gram-positive bacterium Source: Ensembl
  • detection of mechanical stimulus involved in sensory perception of pain Source: Ensembl
  • embryonic digestive tract development Source: DFLAT
  • epithelial cell proliferation involved in salivary gland morphogenesis Source: Ensembl
  • extracellular matrix organization Source: Ensembl
  • extrinsic apoptotic signaling pathway Source: UniProtKB
  • extrinsic apoptotic signaling pathway via death domain receptors Source: UniProtKB
  • glucose metabolic process Source: Ensembl
  • humoral immune response Source: Ensembl
  • inflammatory response Source: UniProtKB
  • intrinsic apoptotic signaling pathway in response to DNA damage Source: Ensembl
  • JNK cascade Source: Ensembl
  • leukocyte tethering or rolling Source: BHF-UCL
  • lipopolysaccharide-mediated signaling pathway Source: UniProtKB
  • MAPK cascade Source: UniProtKB
  • necroptotic signaling pathway Source: UniProtKB
  • negative regulation of alkaline phosphatase activity Source: Ensembl
  • negative regulation of branching involved in lung morphogenesis Source: UniProtKB
  • negative regulation of cell proliferation Source: Ensembl
  • negative regulation of cytokine secretion involved in immune response Source: BHF-UCL
  • negative regulation of extrinsic apoptotic signaling pathway in absence of ligand Source: BHF-UCL
  • negative regulation of fat cell differentiation Source: BHF-UCL
  • negative regulation of gene expression Source: UniProtKB
  • negative regulation of glucose import Source: Ensembl
  • negative regulation of growth of symbiont in host Source: Ensembl
  • negative regulation of interleukin-6 production Source: BHF-UCL
  • negative regulation of L-glutamate transport Source: Ensembl
  • negative regulation of lipid catabolic process Source: BHF-UCL
  • negative regulation of lipid storage Source: BHF-UCL
  • negative regulation of myoblast differentiation Source: Ensembl
  • negative regulation of osteoblast differentiation Source: Ensembl
  • negative regulation of protein complex disassembly Source: UniProtKB
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • negative regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • negative regulation of viral genome replication Source: BHF-UCL
  • osteoclast differentiation Source: Ensembl
  • positive regulation of action potential Source: Ensembl
  • positive regulation of apoptotic process Source: UniProtKB
  • positive regulation of calcidiol 1-monooxygenase activity Source: BHF-UCL
  • positive regulation of chemokine (C-X-C motif) ligand 2 production Source: BHF-UCL
  • positive regulation of chemokine biosynthetic process Source: BHF-UCL
  • positive regulation of chemokine production Source: BHF-UCL
  • positive regulation of chronic inflammatory response to antigenic stimulus Source: Ensembl
  • positive regulation of cysteine-type endopeptidase activity involved in apoptotic process Source: UniProtKB
  • positive regulation of cytokine production Source: BHF-UCL
  • positive regulation of cytokine secretion Source: BHF-UCL
  • positive regulation of ERK1 and ERK2 cascade Source: BHF-UCL
  • positive regulation of fever generation Source: BHF-UCL
  • positive regulation of gene expression Source: AgBase
  • positive regulation of hair follicle development Source: Ensembl
  • positive regulation of heterotypic cell-cell adhesion Source: BHF-UCL
  • positive regulation of humoral immune response mediated by circulating immunoglobulin Source: Ensembl
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: BHF-UCL
  • positive regulation of interferon-gamma production Source: Ensembl
  • positive regulation of interleukin-18 production Source: Ensembl
  • positive regulation of interleukin-6 production Source: Ensembl
  • positive regulation of interleukin-8 biosynthetic process Source: BHF-UCL
  • positive regulation of JUN kinase activity Source: UniProtKB
  • positive regulation of MAP kinase activity Source: UniProtKB
  • positive regulation of membrane protein ectodomain proteolysis Source: BHF-UCL
  • positive regulation of mitotic nuclear division Source: Ensembl
  • positive regulation of mononuclear cell migration Source: BHF-UCL
  • positive regulation of neuron apoptotic process Source: Ensembl
  • positive regulation of NFAT protein import into nucleus Source: MGI
  • positive regulation of NF-kappaB import into nucleus Source: BHF-UCL
  • positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  • positive regulation of nitric oxide biosynthetic process Source: BHF-UCL
  • positive regulation of osteoclast differentiation Source: BHF-UCL
  • positive regulation of peptidyl-serine phosphorylation Source: BHF-UCL
  • positive regulation of phagocytosis Source: AgBase
  • positive regulation of podosome assembly Source: BHF-UCL
  • positive regulation of programmed cell death Source: UniProtKB
  • positive regulation of protein complex assembly Source: BHF-UCL
  • positive regulation of protein complex disassembly Source: UniProtKB
  • positive regulation of protein kinase activity Source: AgBase
  • positive regulation of protein kinase B signaling Source: Ensembl
  • positive regulation of protein localization to cell surface Source: BHF-UCL
  • positive regulation of protein phosphorylation Source: UniProtKB
  • positive regulation of protein transport Source: BHF-UCL
  • positive regulation of sequence-specific DNA binding transcription factor activity Source: BHF-UCL
  • positive regulation of smooth muscle cell proliferation Source: BHF-UCL
  • positive regulation of synaptic transmission Source: Ensembl
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of transcription from RNA polymerase II promoter Source: UniProtKB
  • positive regulation of translational initiation by iron Source: Ensembl
  • positive regulation of vitamin D biosynthetic process Source: BHF-UCL
  • protein import into nucleus, translocation Source: UniProtKB
  • protein kinase B signaling Source: UniProtKB
  • receptor biosynthetic process Source: BHF-UCL
  • regulation of branching involved in salivary gland morphogenesis Source: Ensembl
  • regulation of I-kappaB kinase/NF-kappaB signaling Source: BHF-UCL
  • regulation of immunoglobulin secretion Source: Ensembl
  • regulation of insulin secretion Source: BHF-UCL
  • response to activity Source: Ensembl
  • response to drug Source: Ensembl
  • response to glucocorticoid Source: BHF-UCL
  • response to gold nanoparticle Source: Ensembl
  • response to hypoxia Source: Ensembl
  • response to radiation Source: Ensembl
  • response to salt stress Source: BHF-UCL
  • response to virus Source: BHF-UCL
  • sequestering of triglyceride Source: BHF-UCL
  • skeletal muscle contraction Source: Ensembl
  • transformed cell apoptotic process Source: BHF-UCL
  • tumor necrosis factor-mediated signaling pathway Source: BHF-UCL
Complete GO annotation...

Keywords - Molecular functioni

Cytokine

Enzyme and pathway databases

ReactomeiREACT_1432. TNF signaling.
REACT_27161. Transcriptional regulation of white adipocyte differentiation.
REACT_355072. TNFR1-mediated proapoptotic signaling.

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 Componentsi: Chromosome 6, Unplaced

Organism-specific databases

HGNCiHGNC:11892. TNF.

Subcellular locationi

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini1 – 3535CytoplasmicSequence AnalysisAdd
BLAST
Transmembranei36 – 5621Helical; Signal-anchor for type II membrane proteinSequence AnalysisAdd
BLAST
Topological domaini57 – 233177ExtracellularSequence AnalysisAdd
BLAST

GO - Cellular componenti

  • cell surface Source: BHF-UCL
  • external side of plasma membrane Source: BHF-UCL
  • extracellular region Source: Reactome
  • extracellular space Source: BHF-UCL
  • integral component of plasma membrane Source: BHF-UCL
  • membrane raft Source: BHF-UCL
  • phagocytic cup Source: BHF-UCL
  • plasma membrane Source: Reactome
  • recycling endosome Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Involvement in diseasei

Psoriatic arthritis (PSORAS)1 Publication

Disease susceptibility is associated with variations affecting the gene represented in this entry.

Disease descriptionAn 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).

See also OMIM:607507

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.

Chemistry

DrugBankiDB00051. Adalimumab.
DB01427. Amrinone.
DB08904. Certolizumab pegol.
DB00608. Chloroquine.
DB01407. Clenbuterol.
DB00668. Epinephrine.
DB00005. Etanercept.
DB01296. Glucosamine.
DB06674. golimumab.
DB00065. Infliximab.
DB08910. Pomalidomide.
DB01411. Pranlukast.
DB00852. Pseudoephedrine.
DB01041. Thalidomide.

Polymorphism and mutation databases

BioMutaiTNF.
DMDMi135934.

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

BgeeiP01375.
CleanExiHS_TNF.
ExpressionAtlasiP01375. baseline and differential.
GenevestigatoriP01375.

Organism-specific databases

HPAiHPA064998.

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. 88 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 – 946Combined sources
Beta strandi96 – 983Combined sources
Beta strandi99 – 1013Combined sources
Beta strandi106 – 1083Combined sources
Beta strandi112 – 1143Combined sources
Beta strandi118 – 1203Combined sources
Beta strandi123 – 1253Combined sources
Beta strandi130 – 14415Combined sources
Beta strandi146 – 1483Combined sources
Beta strandi152 – 1598Combined sources
Helixi161 – 1633Combined sources
Beta strandi167 – 1748Combined sources
Beta strandi177 – 1793Combined sources
Beta strandi182 – 1854Combined sources
Beta strandi189 – 20214Combined sources
Beta strandi207 – 2137Combined sources
Helixi215 – 2173Combined sources
Beta strandi221 – 2233Combined sources
Beta strandi225 – 2328Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
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[»]
4TWTX-ray2.85A/B/C/D77-233[»]
5TSWX-ray2.50A/B/C/D/E/F84-233[»]
ProteinModelPortaliP01375.
SMRiP01375. Positions 85-233.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP01375.

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

        10         20         30         40         50
MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL
60 70 80 90 100
LHFGVIGPQR EEFPRDLSLI SPLAQAVRSS SRTPSDKPVA HVVANPQAEG
110 120 130 140 150
QLQWLNRRAN ALLANGVELR DNQLVVPSEG LYLIYSQVLF KGQGCPSTHV
160 170 180 190 200
LLTHTISRIA VSYQTKVNLL SAIKSPCQRE TPEGAEAKPW YEPIYLGGVF
210 220 230
QLEKGDRLSA EINRPDYLDF AESGQVYFGI IAL
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. Curated
The sequence CAA75070.1 differs from that shown. Reason: Erroneous gene model prediction. Curated

Experimental Info

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti63 – 631F → S in AAA61198 (PubMed:3856324).Curated
Sequence conflicti84 – 863PSD → VNR in AAF71992 (Ref. 17) Curated
Sequence conflicti183 – 1831E → R in AAC03542 (Ref. 16) Curated

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:
EMBLi
GenBanki
DDBJi
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.

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:
EMBLi
GenBanki
DDBJi
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.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
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[»]
4TWTX-ray2.85A/B/C/D77-233[»]
5TSWX-ray2.50A/B/C/D/E/F84-233[»]
ProteinModelPortaliP01375.
SMRiP01375. Positions 85-233.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi112979. 88 interactions.
DIPiDIP-2895N.
IntActiP01375. 30 interactions.
MINTiMINT-1131842.
STRINGi9606.ENSP00000392858.

Chemistry

BindingDBiP01375.
ChEMBLiCHEMBL1825.
DrugBankiDB00051. Adalimumab.
DB01427. Amrinone.
DB08904. Certolizumab pegol.
DB00608. Chloroquine.
DB01407. Clenbuterol.
DB00668. Epinephrine.
DB00005. Etanercept.
DB01296. Glucosamine.
DB06674. golimumab.
DB00065. Infliximab.
DB08910. Pomalidomide.
DB01411. Pranlukast.
DB00852. Pseudoephedrine.
DB01041. Thalidomide.
GuidetoPHARMACOLOGYi2635.

PTM databases

PhosphoSiteiP01375.
UniCarbKBiP01375.

Polymorphism and mutation databases

BioMutaiTNF.
DMDMi135934.

Proteomic databases

PaxDbiP01375.
PRIDEiP01375.

Protocols and materials databases

DNASUi7124.
Structural Biology KnowledgebaseSearch...

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.

Organism-specific databases

CTDi7124.
GeneCardsiGC06P031543.
GC06Pj31530.
GC06Pk31525.
GC06Pl31582.
GC06Pm31619.
GC06Pn31533.
GC06Po31533.
H-InvDBHIX0165948.
HGNCiHGNC:11892. TNF.
HPAiHPA064998.
MIMi191160. gene.
607507. phenotype.
610424. phenotype.
611162. phenotype.
neXtProtiNX_P01375.
Orphaneti40050. Adult psoriatic arthritis.
PharmGKBiPA435.
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

ReactomeiREACT_1432. TNF signaling.
REACT_27161. Transcriptional regulation of white adipocyte differentiation.
REACT_355072. TNFR1-mediated proapoptotic signaling.

Miscellaneous databases

ChiTaRSiTNF. human.
EvolutionaryTraceiP01375.
GeneWikiiTumor_necrosis_factor-alpha.
GenomeRNAii7124.
NextBioi27879.
PMAP-CutDBP01375.
PROiP01375.
SOURCEiSearch...

Gene expression databases

BgeeiP01375.
CleanExiHS_TNF.
ExpressionAtlasiP01375. baseline and differential.
GenevestigatoriP01375.

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]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  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. "Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-alpha in rheumatoid arthritis."
    Nie H., Zheng Y., Li R., Guo T.B., He D., Fang L., Liu X., Xiao L., Chen X., Wan B., Chin Y.E., Zhang J.Z.
    Nat. Med. 19:322-328(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION.
  27. Cited for: X-RAY CRYSTALLOGRAPHY (2.9 ANGSTROMS).
  28. "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).
  29. "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).
  30. "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.
  31. "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.
  32. "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.
  33. "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: May 27, 2015
This is version 205 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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into Uniref entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.