P01375 (TNFA_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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:

1. Tumor necrosis factor, membrane form
   Alternative name(s):
   N-terminal fragment
   Short name=NTF
2. Intracellular domain 1
   Short name=ICD1
3. Intracellular domain 2
   Short name=ICD2
4. C-domain 1
5. C-domain 2
6. Tumor necrosis factor, soluble form

Gene names

Name:	TNF
Synonyms:	TNFA, TNFSF2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	233 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.24 The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. Ref.24
Subunit structure	Homotrimer. Interacts with SPPL2B. Ref.25
Subcellular location	Cell membrane; Single-pass type II membrane protein Ref.24. Tumor necrosis factor, membrane form: Membrane; Single-pass type II membrane protein Ref.24. Tumor necrosis factor, soluble form: Secreted Ref.24. C-domain 1: Secreted Ref.24. C-domain 2: Secreted Ref.24.
Post-translational modification	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. 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. Ref.18 Ref.19 O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid. Ref.15
Polymorphism	Genetic variations in TNF influence susceptibility to hepatitis B virus (HBV) infection [MIM:610424]. Genetic variations in TNF are involved in susceptibility to malaria [MIM:611162].
Involvement in disease	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 rheumatoidlike 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). Note: Disease susceptibility is associated with variations affecting the gene represented in this entry.
Sequence similarities	Belongs to the tumor necrosis factor family.
Sequence caution	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.

Ontologies

Keywords
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Polymorphism
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Cytokine
PTM	Disulfide bond Glycoprotein Lipoprotein Myristate Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	JNK cascade Inferred from electronic annotation. Source: Compara MAPK cascade Inferred from mutant phenotype PubMed 21147091. Source: UniProtKB activation of MAPK activity Inferred from direct assay PubMed 10748004. Source: BHF-UCL activation of MAPKKK activity Inferred from direct assay PubMed 15310755. Source: BHF-UCL activation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from direct assay PubMed 16723520. Source: UniProtKB activation of necroptosis by extracellular signals Inferred from direct assay PubMed 11101870. Source: BHF-UCL calcium-mediated signaling Inferred from electronic annotation. Source: Compara cell activation Inferred from electronic annotation. Source: Compara cellular response to amino acid stimulus Inferred from electronic annotation. Source: Compara cellular response to nicotine Inferred from direct assay PubMed 18676776. Source: UniProtKB chronic inflammatory response to antigenic stimulus Inferred from mutant phenotype PubMed 14512626. Source: BHF-UCL defense response to Gram-positive bacterium Inferred from electronic annotation. Source: Compara embryonic digestive tract development Inferred from expression pattern PubMed 20875417. Source: DFLAT epithelial cell proliferation involved in salivary gland morphogenesis Inferred from electronic annotation. Source: Compara extracellular matrix organization Inferred from electronic annotation. Source: Compara extrinsic apoptotic signaling pathway via death domain receptors Inferred from direct assay PubMed 18676776. Source: UniProtKB glucose metabolic process Inferred from electronic annotation. Source: Compara humoral immune response Inferred from electronic annotation. Source: Compara induction of apoptosis Inferred from direct assay PubMed 18202225. Source: BHF-UCL leukocyte tethering or rolling Inferred from direct assay PubMed 10820279. Source: BHF-UCL lipopolysaccharide-mediated signaling pathway Inferred from direct assay PubMed 21147091. Source: UniProtKB necrotic cell death Inferred from direct assay PubMed 11101870. Source: BHF-UCL negative regulation of L-glutamate transport Inferred from electronic annotation. Source: Compara negative regulation of alkaline phosphatase activity Inferred from electronic annotation. Source: Compara negative regulation of apoptotic process Inferred from direct assay PubMed 10666185PubMed 10748004. Source: BHF-UCL negative regulation of branching involved in lung morphogenesis Inferred from direct assay PubMed 17350185. Source: UniProtKB negative regulation of cell proliferation Inferred from electronic annotation. Source: Compara negative regulation of cytokine secretion involved in immune response Inferred from direct assay PubMed 10443688. Source: BHF-UCL negative regulation of fat cell differentiation Non-traceable author statement PubMed 16464856. Source: BHF-UCL negative regulation of glucose import Inferred from electronic annotation. Source: Compara negative regulation of growth of symbiont in host Inferred from electronic annotation. Source: Compara negative regulation of interleukin-6 production Inferred from direct assay PubMed 10443688. Source: BHF-UCL negative regulation of lipid catabolic process Inferred from direct assay PubMed 19032770. Source: BHF-UCL negative regulation of lipid storage Non-traceable author statement PubMed 16464856. Source: BHF-UCL negative regulation of osteoblast differentiation Inferred from electronic annotation. Source: Compara negative regulation of protein complex disassembly Inferred from direct assay PubMed 17389591. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 15345745. Source: UniProtKB negative regulation of viral genome replication Inferred from direct assay PubMed 10490959. Source: BHF-UCL organ morphogenesis Inferred from electronic annotation. Source: Compara osteoclast differentiation Inferred from electronic annotation. Source: Compara positive regulation of ERK1 and ERK2 cascade Non-traceable author statement PubMed 18606301. Source: BHF-UCL positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from direct assay PubMed 15310755PubMed 17922812. Source: BHF-UCL positive regulation of JNK cascade Inferred from electronic annotation. Source: Compara positive regulation of JUN kinase activity Inferred from direct assay PubMed 17389591. Source: UniProtKB positive regulation of NF-kappaB import into nucleus Inferred from direct assay PubMed 17922812. Source: BHF-UCL positive regulation of NF-kappaB transcription factor activity Inferred from direct assay PubMed 16280327PubMed 16611992. Source: UniProtKB positive regulation of NFAT protein import into nucleus Inferred from direct assay PubMed 16803872. Source: MGI positive regulation of calcidiol 1-monooxygenase activity Inferred from direct assay PubMed 1690216. Source: BHF-UCL positive regulation of chemokine (C-X-C motif) ligand 2 production Inferred from direct assay PubMed 20551324. Source: BHF-UCL positive regulation of chemokine biosynthetic process Inferred from direct assay PubMed 10490959. Source: BHF-UCL positive regulation of chronic inflammatory response to antigenic stimulus Inferred from electronic annotation. Source: Compara positive regulation of cytokine secretion Inferred from direct assay PubMed 10443688. Source: BHF-UCL positive regulation of fever generation Inferred from sequence or structural similarity. Source: BHF-UCL positive regulation of hair follicle development Inferred from electronic annotation. Source: Compara positive regulation of heterotypic cell-cell adhesion Inferred from direct assay PubMed 10604883PubMed 20551324. Source: BHF-UCL positive regulation of humoral immune response mediated by circulating immunoglobulin Inferred from electronic annotation. Source: Compara positive regulation of interferon-gamma production Inferred from electronic annotation. Source: Compara positive regulation of interleukin-6 production Inferred from electronic annotation. Source: Compara positive regulation of interleukin-8 biosynthetic process Inferred from direct assay PubMed 20551324. Source: BHF-UCL positive regulation of membrane protein ectodomain proteolysis Inferred from direct assay PubMed 18373975. Source: BHF-UCL positive regulation of mitosis Inferred from electronic annotation. Source: Compara positive regulation of mononuclear cell migration Non-traceable author statement PubMed 21319131. Source: BHF-UCL positive regulation of neuron apoptotic process Inferred from electronic annotation. Source: Compara positive regulation of nitric oxide biosynthetic process Inferred from direct assay PubMed 8383325. Source: BHF-UCL positive regulation of osteoclast differentiation Inferred from direct assay PubMed 17888176. Source: BHF-UCL positive regulation of peptidyl-serine phosphorylation Inferred from direct assay PubMed 17389591PubMed 18440775. Source: BHF-UCL positive regulation of podosome assembly Inferred from direct assay PubMed 15220135. Source: BHF-UCL positive regulation of protein complex disassembly Inferred from direct assay PubMed 17389591. Source: UniProtKB positive regulation of protein kinase B signaling cascade Inferred from electronic annotation. Source: Compara positive regulation of protein localization to cell surface Inferred from direct assay PubMed 19366699. Source: BHF-UCL positive regulation of smooth muscle cell proliferation Inferred from direct assay PubMed 16518841. Source: BHF-UCL positive regulation of synaptic transmission Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from direct assay PubMed 15345745. Source: UniProtKB positive regulation of translational initiation by iron Inferred from electronic annotation. Source: Compara positive regulation of vitamin D biosynthetic process Inferred from direct assay PubMed 1690216. Source: BHF-UCL protein import into nucleus, translocation Inferred from direct assay PubMed 16280327. Source: UniProtKB protein kinase B signaling cascade Inferred from mutant phenotype PubMed 21147091. Source: UniProtKB receptor biosynthetic process Inferred from direct assay PubMed 10443688. Source: BHF-UCL regulation of branching involved in salivary gland morphogenesis Inferred from electronic annotation. Source: Compara regulation of immunoglobulin secretion Inferred from electronic annotation. Source: Compara regulation of insulin secretion Inferred from direct assay PubMed 8383325. Source: BHF-UCL response to activity Inferred from electronic annotation. Source: Compara response to drug Inferred from electronic annotation. Source: Compara response to glucocorticoid stimulus Inferred from direct assay PubMed 10443688. Source: BHF-UCL response to hypoxia Inferred from electronic annotation. Source: Compara response to mechanical stimulus Inferred from electronic annotation. Source: Compara response to salt stress Traceable author statement PubMed 18355445. Source: BHF-UCL response to virus Inferred from direct assay PubMed 10490959. Source: BHF-UCL sequestering of triglyceride Inferred from direct assay PubMed 19032770. Source: BHF-UCL skeletal muscle contraction Inferred from electronic annotation. Source: Compara transformed cell apoptotic process Inferred from direct assay Ref.3. Source: BHF-UCL tumor necrosis factor-mediated signaling pathway Inferred from mutant phenotype PubMed 10748004. Source: BHF-UCL
Cellular_component	external side of plasma membrane Inferred from sequence or structural similarity. Source: BHF-UCL extracellular space Inferred from direct assay PubMed 10443688PubMed 18355445Ref.6. Source: BHF-UCL integral to plasma membrane Inferred from direct assay PubMed 18355445. Source: BHF-UCL membrane raft Inferred from direct assay PubMed 17010968. Source: BHF-UCL phagocytic cup Inferred from sequence or structural similarity. Source: BHF-UCL recycling endosome Inferred from sequence or structural similarity. Source: BHF-UCL
Molecular_function	cytokine activity Inferred from direct assay PubMed 10748004. Source: BHF-UCL identical protein binding Inferred from direct assay PubMed 14512626. Source: BHF-UCL transcription regulatory region DNA binding Inferred from direct assay PubMed 17350185. Source: UniProtKB tumor necrosis factor receptor binding Inferred from direct assay PubMed 14512626. Source: BHF-UCL
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
TNFRSF1A	P19438	6	EBI-359977,EBI-299451

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 233

233

Tumor necrosis factor, membrane form

PRO_0000034423

Chain

1 – 39

39

Intracellular domain 1

PRO_0000417231

Chain

1 – 35

35

Intracellular domain 2

PRO_0000417232

Chain

50 – ?

C-domain 1

PRO_0000417233

Chain

52 – ?

C-domain 2

PRO_0000417234

Chain

77 – 233

157

Tumor necrosis factor, soluble form Ref.5

PRO_0000034424

Regions

Topological domain

1 – 35

35

Cytoplasmic Potential

Transmembrane

36 – 56

21

Helical; Signal-anchor for type II membrane protein; Potential

Topological domain

57 – 233

177

Extracellular Potential

Sites

Site

35 – 36

2

Cleavage; by SPPL2A or SPPL2B

Site

39 – 40

2

Cleavage; by SPPL2A or SPPL2B

Site

49 – 50

2

Cleavage; by SPPL2A or SPPL2B

Site

51 – 52

2

Cleavage; by SPPL2A or SPPL2B

Site

76 – 77

2

Cleavage; by ADAM17

Amino acid modifications

Modified residue

2

1

Phosphoserine; by CK1 Probable

Lipidation

19

1

N6-myristoyl lysine Ref.21

Lipidation

20

1

N6-myristoyl lysine Ref.21

Glycosylation

80

1

O-linked (GalNAc...); in soluble form Ref.15

Disulfide bond

145 ↔ 177

Natural variations

Natural variant

84

1

P → L. Ref.13
Corresponds to variant rs4645843 [ dbSNP | Ensembl ].

VAR_019378

Natural variant

94

1

A → T.
Corresponds to variant rs1800620 [ dbSNP | Ensembl ].

VAR_011927

Experimental info

Mutagenesis

105

1

L → S: Low activity.

Mutagenesis

108

1

R → W: Biologically inactive.

Mutagenesis

112

1

L → F: Biologically inactive.

Mutagenesis

160

1

A → V: Biologically inactive.

Mutagenesis

162

1

S → F: Biologically inactive.

Mutagenesis

167

1

V → A or D: Biologically inactive.

Mutagenesis

222

1

E → K: Biologically inactive.

Sequence conflict

63

1

F → S in AAA61198. Ref.5

Sequence conflict

84 – 86

3

PSD → VNR in AAF71992. Ref.17

Sequence conflict

183

1

E → R in AAC03542. Ref.16

Secondary structure

1

.

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233

Helix Strand Turn

Details...

Beta strand

89 – 94

6

Beta strand

96 – 98

3

Beta strand

99 – 101

3

Beta strand

106 – 108

3

Beta strand

112 – 114

3

Beta strand

118 – 120

3

Beta strand

123 – 125

3

Beta strand

130 – 144

15

Beta strand

146 – 148

3

Beta strand

152 – 159

8

Helix

161 – 163

3

Beta strand

167 – 174

8

Beta strand

177 – 179

3

Beta strand

182 – 185

4

Beta strand

189 – 202

14

Beta strand

207 – 213

7

Helix

215 – 217

3

Beta strand

221 – 223

3

Beta strand

225 – 232

8

Sequences

	Sequence		Length	Mass (Da)
	P01375 [UniParc]. Last modified July 21, 1986. Version 1. Checksum: 3DF90F96C9031FFE	FASTA	233	25,644
	10 20 30 40 50 60 MSTESMIRDV ELAEEALPKK TGGPQGSRRC LFLSLFSFLI VAGATTLFCL LHFGVIGPQR 70 80 90 100 110 120 EEFPRDLSLI SPLAQAVRSS SRTPSDKPVA HVVANPQAEG QLQWLNRRAN ALLANGVELR 130 140 150 160 170 180 DNQLVVPSEG LYLIYSQVLF KGQGCPSTHV LLTHTISRIA VSYQTKVNLL SAIKSPCQRE 190 200 210 220 230 TPEGAEAKPW YEPIYLGGVF QLEKGDRLSA EINRPDYLDF AESGQVYFGI IAL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[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]	"Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha." Moss M.L., Jin S.-L.C., Milla M.E., Burkhart W., Carter H.L., Chen W.-J., Clay W.C., Didsbury J.R., Hassler D., Hoffman C.R., Kost T.A., Lambert M.H., Leesnitzer M.A., McCauley P., McGeehan G., Mitchell J., Moyer M., Pahel G. , Rocque W., Overton L.K., Schoenen F., Seaton T., Su J.-L., Warner J., Willard D., Becherer J.D. Nature 385:733-736(1997) [PubMed] [Europe PMC] [Abstract] 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]	"Structure of tumour necrosis factor." Jones E.Y., Stuart D.I., Walker N.P. Nature 338:225-228(1989) [PubMed] [Europe PMC] [Abstract] 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.
+	Additional computationally mapped references.

Web resources

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

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

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.

IPI

IPI00001671.

PIR

QWHUN. A93585.

RefSeq

NP_000585.2. NM_000594.3.

UniGene

Hs.241570.

3D structure databases

PDBe
RCSB PDB
PDBj

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	[»]
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	[»]

ProteinModelPortal

P01375.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-2895N.

IntAct

P01375. 23 interactions.

MINT

MINT-1131842.

STRING

9606.ENSP00000392858.

PTM databases

GlycoSuiteDB

P01375.

PhosphoSite

P01375.

Polymorphism databases

DMDM

135934.

Proteomic databases

PaxDb

P01375.

PRIDE

P01375.

Protocols and materials databases

DNASU

7124.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000376122; ENSP00000365290; ENSG00000204490.
ENST00000383496; ENSP00000372988; ENSG00000206439.
ENST00000412275; ENSP00000392858; ENSG00000228321.
ENST00000420425; ENSP00000410668; ENSG00000228849.
ENST00000443707; ENSP00000389492; ENSG00000230108.
ENST00000448781; ENSP00000389490; ENSG00000223952.
ENST00000449264; ENSP00000398698; ENSG00000232810.

GeneID

7124.

KEGG

hsa:7124.

UCSC

uc003nui.3. human.

Organism-specific databases

CTD

7124.

GeneCards

GC06P031543.

H-InvDB

HIX0165948.

HGNC

HGNC:11892. TNF.

MIM

191160. gene.
607507. phenotype.
610424. phenotype.
611162. phenotype.

neXtProt

NX_P01375.

Orphanet

40050. Adult psoriatic arthritis.

PharmGKB

PA435.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG40413.

HOGENOM

HOG000048729.

HOVERGEN

HBG012516.

InParanoid

P01375.

KO

K03156.

OMA

WYEPIYL.

OrthoDB

EOG4JWVFT.

PhylomeDB

P01375.

Enzyme and pathway databases

Pathway_Interaction_DB

amb2_neutrophils_pathway. amb2 Integrin signaling.
angiopoietinreceptor_pathway. Angiopoietin receptor Tie2-mediated signaling.
nfat_tfpathway. Calcineurin-regulated NFAT-dependent transcription in lymphocytes.
nfkappabcanonicalpathway. Canonical NF-kappaB pathway.
caspase_pathway. Caspase cascade in apoptosis.
anthraxpathway. Cellular roles of Anthrax toxin.
ceramidepathway. Ceramide signaling pathway.
cd8tcrdownstreampathway. Downstream signaling in naive CD8+ T cells.
hivnefpathway. HIV-1 Nef: Negative effector of Fas and TNF-alpha.
il23pathway. IL23-mediated signaling events.
il27pathway. IL27-mediated signaling events.
rxr_vdr_pathway. RXR and RAR hetrodimerization with other nuclear receptor.
hdac_classi_pathway. Signaling events mediated by HDAC Class I.
tnfpathway. TNF receptor signaling pathway.

Reactome

REACT_578. Apoptosis.

Gene expression databases

ArrayExpress

P01375.

Bgee

P01375.

CleanEx

HS_TNF.

Genevestigator

P01375.

GermOnline

ENSG00000204490. Homo sapiens.

Family and domain databases

Gene3D

2.60.120.40. 1 hit.

InterPro

IPR006052. TNF.
IPR006053. TNF_a/b/c.
IPR002959. TNF_alpha.
IPR021184. TNF_CS.
IPR008983. Tumour_necrosis_fac-like_dom.
[Graphical view]

Pfam

PF00229. TNF. 1 hit.
[Graphical view]

PRINTS

PR01234. TNECROSISFCT.
PR01235. TNFALPHA.

SMART

SM00207. TNF. 1 hit.
[Graphical view]

SUPFAM

SSF49842. TNF_like. 1 hit.

PROSITE

PS00251. TNF_1. 1 hit.
PS50049. TNF_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P01375.

ChEMBL

CHEMBL1825.

ChiTaRS

TNF. human.

DrugBank

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.

EvolutionaryTrace

P01375.

GenomeRNAi

7124.

NextBio

27879.

PMAP-CutDB

P01375.

SOURCE

Search...

Entry information

Entry name

TNFA_HUMAN

Accession

Primary (citable) accession number: P01375
Secondary accession number(s): O43647, Q9P1Q2, Q9UIV3

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 21, 1986
Last sequence update:	July 21, 1986
Last modified:	May 29, 2013
This is version 183 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.