UniProtKB - P01375 (TNFA_HUMAN)

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History
Entry version 238 (18 Jul 2018)
Sequence version 1 (21 Jul 1986)
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Protein

Tumor necrosis factor

Gene

TNF

Organism

Homo sapiens (Human)

Status

Reviewed-Annotation score: -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). Key mediator of cell death in the anticancer action of BCG-stimulated neutrophils in combination with DIABLO/SMAC mimetic in the RT4v6 bladder cancer cell line (PubMed:22517918).3 Publications

The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells.1 Publication

GO - Molecular functionⁱ

cytokine activity
Source: BHF-UCL
Inferred from direct assayⁱ
- 10748004
identical protein binding
Source: BHF-UCL
Inferred from direct assayⁱ
- 14512626
protease binding
Source: BHF-UCL
Inferred from physical interactionⁱ
- 12777399
transcription regulatory region DNA binding
Source: UniProtKB
Inferred from direct assayⁱ
- 17350185
tumor necrosis factor receptor binding
Source: BHF-UCL
Inferred from direct assayⁱ
- 14512626

View the complete GO annotation on QuickGO ...

GO - Biological processⁱ

activation of cysteine-type endopeptidase activity involved in apoptotic process
Source: UniProtKB
Inferred from direct assayⁱ
- 16723520
activation of MAPK activity
Source: BHF-UCL
Inferred from direct assayⁱ
- 10748004
activation of MAPKKK activity
Source: BHF-UCL
Inferred from direct assayⁱ
- 15310755
cellular response to amino acid stimulus Source: Ensembl
cellular response to nicotine
Source: UniProtKB
Inferred from direct assayⁱ
- 18676776
cellular response to organic cyclic compound
Source: UniProtKB
Inferred from direct assayⁱ
- 21147091
chronic inflammatory response to antigenic stimulus
Source: BHF-UCL
Inferred from mutant phenotypeⁱ
- 14512626
cortical actin cytoskeleton organization
Source: UniProtKB
Inferred from direct assayⁱ
- 25816133
cytokine-mediated signaling pathway Source: Reactome
death-inducing signaling complex assembly Source: Reactome
defense response to Gram-positive bacterium Source: Ensembl
embryonic digestive tract development
Source: DFLAT
Inferred from expression patternⁱ
- 20875417
endothelial cell apoptotic process Source: Ensembl
epithelial cell proliferation involved in salivary gland morphogenesis Source: Ensembl
extracellular matrix organization Source: Ensembl
extrinsic apoptotic signaling pathway
Source: UniProtKB
Inferred from direct assayⁱ
- 11577081
- 16611992
extrinsic apoptotic signaling pathway via death domain receptors
Source: UniProtKB
Inferred from direct assayⁱ
- 18676776
glucose metabolic process Source: Ensembl
humoral immune response Source: Ensembl
I-kappaB kinase/NF-kappaB signaling Source: Reactome
inflammatory response
Source: UniProtKB
Inferred from direct assayⁱ
- 21147091
intrinsic apoptotic signaling pathway in response to DNA damage Source: Ensembl
JNK cascade Source: Ensembl
leukocyte tethering or rolling
Source: BHF-UCL
Inferred from direct assayⁱ
- 10820279
lipopolysaccharide-mediated signaling pathway
Source: UniProtKB
Inferred from direct assayⁱ
- 21147091
MAPK cascade
Source: UniProtKB
Inferred from mutant phenotypeⁱ
- 21147091
necroptotic signaling pathway
Source: UniProtKB
Inferred from direct assayⁱ
negative regulation of alkaline phosphatase activity Source: Ensembl
negative regulation of bicellular tight junction assembly
Source: UniProtKB
Inferred from direct assayⁱ
- 25816133
negative regulation of branching involved in lung morphogenesis
Source: UniProtKB
Inferred from direct assayⁱ
- 17350185
negative regulation of cytokine secretion involved in immune response
Source: BHF-UCL
Inferred from direct assayⁱ
- 10443688
negative regulation of endothelial cell proliferation Source: Ensembl
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand
Source: BHF-UCL
Inferred from direct assayⁱ
- 10748004
- 10666185
negative regulation of fat cell differentiation
Source: BHF-UCL
Non-traceable author statementⁱ
- 16464856
negative regulation of gene expression
Source: UniProtKB
Inferred from direct assayⁱ
- 15345745
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
Inferred from direct assayⁱ
- 10443688
negative regulation of lipid catabolic process
Source: BHF-UCL
Inferred from direct assayⁱ
- 19032770
negative regulation of lipid storage
Source: BHF-UCL
Non-traceable author statementⁱ
- 16464856
negative regulation of mitotic cell cycle Source: Ensembl
negative regulation of myoblast differentiation Source: Ensembl
negative regulation of myosin-light-chain-phosphatase activity
Source: UniProtKB
Inferred from direct assayⁱ
- 25816133
negative regulation of osteoblast differentiation Source: Ensembl
negative regulation of protein complex disassembly
Source: UniProtKB
Inferred from direct assayⁱ
- 17389591
negative regulation of transcription, DNA-templated
Source: UniProtKB
Inferred from direct assayⁱ
- 17350185
- 16895791
negative regulation of transcription by RNA polymerase II
Source: UniProtKB
Inferred from direct assayⁱ
- 15345745
negative regulation of viral genome replication
Source: BHF-UCL
Inferred from direct assayⁱ
- 10490959
osteoclast differentiation Source: Ensembl
positive regulation of apoptotic process
Source: UniProtKB
Inferred from direct assayⁱ
positive regulation of blood microparticle formation
Source: BHF-UCL
Inferred from direct assayⁱ
- 24998411
positive regulation of calcidiol 1-monooxygenase activity
Source: BHF-UCL
Inferred from direct assayⁱ
- 1690216
positive regulation of calcineurin-NFAT signaling cascade
Source: MGI
Inferred from direct assayⁱ
- 16803872
positive regulation of cell adhesion
Source: UniProtKB
Inferred from mutant phenotypeⁱ
- 23892569
positive regulation of ceramide biosynthetic process Source: Reactome
positive regulation of chemokine (C-X-C motif) ligand 2 production
Source: BHF-UCL
Inferred from direct assayⁱ
- 20551324
positive regulation of chemokine biosynthetic process
Source: BHF-UCL
Inferred from direct assayⁱ
- 10490959
positive regulation of chemokine production
Source: BHF-UCL
Inferred from direct assayⁱ
- 10490959
positive regulation of chronic inflammatory response to antigenic stimulus Source: Ensembl
positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
Source: UniProtKB
Inferred from direct assayⁱ
- 11577081
positive regulation of cytokine production
Source: BHF-UCL
Inferred from direct assayⁱ
- 17922812
positive regulation of cytokine secretion
Source: BHF-UCL
Inferred from direct assayⁱ
- 10443688
positive regulation of DNA binding transcription factor activity
Source: BHF-UCL
Inferred from direct assayⁱ
- 10748004
positive regulation of ERK1 and ERK2 cascade
Source: BHF-UCL
Non-traceable author statementⁱ
- 18606301
positive regulation of fever generation Source: BHF-UCL
positive regulation of gene expression
Source: UniProtKB
Inferred from direct assayⁱ
- 11085990
- 23817958
positive regulation of hair follicle development Source: Ensembl
positive regulation of heterotypic cell-cell adhesion
Source: BHF-UCL
Inferred from direct assayⁱ
- 20551324
- 10604883
positive regulation of humoral immune response mediated by circulating immunoglobulin Source: Ensembl
positive regulation of I-kappaB kinase/NF-kappaB signaling
Source: BHF-UCL
Inferred from direct assayⁱ
- 15310755
- 17922812
positive regulation of interferon-gamma production Source: Ensembl
positive regulation of interleukin-6 production Source: Ensembl
positive regulation of interleukin-8 biosynthetic process
Source: BHF-UCL
Inferred from direct assayⁱ
- 20551324
positive regulation of interleukin-8 production
Source: UniProtKB
Inferred from mutant phenotypeⁱ
- 24790089
positive regulation of JUN kinase activity
Source: UniProtKB
Inferred from direct assayⁱ
- 17389591
positive regulation of leukocyte adhesion to arterial endothelial cell
Source: BHF-UCL
Inferred from direct assayⁱ
- 22267480
positive regulation of leukocyte adhesion to vascular endothelial cell
Source: BHF-UCL
Inferred from direct assayⁱ
- 26371161
positive regulation of MAP kinase activity
Source: UniProtKB
Inferred from direct assayⁱ
- 17389591
positive regulation of membrane protein ectodomain proteolysis
Source: BHF-UCL
Inferred from direct assayⁱ
- 18373975
positive regulation of mononuclear cell migration
Source: BHF-UCL
Non-traceable author statementⁱ
- 21319131
positive regulation of NF-kappaB transcription factor activity
Source: UniProtKB
Inferred from direct assayⁱ
positive regulation of NIK/NF-kappaB signaling
Source: UniProtKB
Inferred from direct assayⁱ
- 20041225
positive regulation of nitric oxide biosynthetic process
Source: BHF-UCL
Inferred from direct assayⁱ
- 8383325
positive regulation of osteoclast differentiation
Source: BHF-UCL
Inferred from direct assayⁱ
- 17888176
positive regulation of peptidyl-serine phosphorylation
Source: BHF-UCL
Inferred from direct assayⁱ
- 17389591
- 18440775
positive regulation of phagocytosis
Source: AgBase
Inferred from mutant phenotypeⁱ
- 18201371
positive regulation of podosome assembly
Source: BHF-UCL
Inferred from direct assayⁱ
- 15220135
positive regulation of programmed cell death
Source: UniProtKB
Inferred from direct assayⁱ
- 16611992
positive regulation of protein catabolic process
Source: AgBase
Inferred from direct assayⁱ
- 18632959
positive regulation of protein complex assembly
Source: BHF-UCL
Inferred from direct assayⁱ
- 12813029
positive regulation of protein complex disassembly
Source: UniProtKB
Inferred from direct assayⁱ
- 17389591
positive regulation of protein kinase activity
Source: AgBase
Inferred from direct assayⁱ
- 11821416
positive regulation of protein kinase B signaling Source: Ensembl
positive regulation of protein localization to cell surface
Source: BHF-UCL
Inferred from direct assayⁱ
- 19366699
positive regulation of protein phosphorylation
Source: UniProtKB
Inferred from direct assayⁱ
- 16723520
- 17389591
positive regulation of protein transport
Source: BHF-UCL
Inferred from direct assayⁱ
- 15310755
positive regulation of smooth muscle cell proliferation
Source: BHF-UCL
Inferred from direct assayⁱ
- 16518841
positive regulation of superoxide dismutase activity
Source: BHF-UCL
Inferred from direct assayⁱ
- 22836756
positive regulation of transcription, DNA-templated
Source: UniProtKB
Inferred from direct assayⁱ
- 17350185
positive regulation of transcription by RNA polymerase II
Source: UniProtKB
Inferred from direct assayⁱ
- 15345745
positive regulation of translational initiation by iron Source: Ensembl
positive regulation of vascular smooth muscle cell proliferation Source: Ensembl
positive regulation of vitamin D biosynthetic process
Source: BHF-UCL
Inferred from direct assayⁱ
- 1690216
protein import into nucleus, translocation
Source: UniProtKB
Inferred from direct assayⁱ
- 16280327
protein kinase B signaling
Source: UniProtKB
Inferred from mutant phenotypeⁱ
- 21147091
protein localization to plasma membrane
Source: UniProtKB
Inferred from direct assayⁱ
- 25816133
receptor biosynthetic process
Source: BHF-UCL
Inferred from direct assayⁱ
- 10443688
regulation of branching involved in salivary gland morphogenesis Source: Ensembl
regulation of establishment of endothelial barrier
Source: UniProtKB
Inferred from direct assayⁱ
- 25816133
regulation of I-kappaB kinase/NF-kappaB signaling
Source: BHF-UCL
Inferred from direct assayⁱ
- 10748004
regulation of immunoglobulin secretion Source: Ensembl
regulation of insulin secretion
Source: BHF-UCL
Inferred from direct assayⁱ
- 8383325
regulation of tumor necrosis factor-mediated signaling pathway Source: Reactome
response to glucocorticoid
Source: BHF-UCL
Inferred from direct assayⁱ
- 10443688
response to salt stress
Source: BHF-UCL
Traceable author statementⁱ
- 18355445
response to virus
Source: BHF-UCL
Inferred from direct assayⁱ
- 10490959
sequestering of triglyceride
Source: BHF-UCL
Inferred from direct assayⁱ
- 19032770
tumor necrosis factor-mediated signaling pathway
Source: BHF-UCL
Inferred from mutant phenotypeⁱ
- 10748004

View the complete GO annotation on QuickGO ...

Keywordsⁱ

Molecular function	Cytokine

Molecular function

Cytokine

Enzyme and pathway databases

Reactomeⁱ	R-HSA-381340 Transcriptional regulation of white adipocyte differentiation R-HSA-5357786 TNFR1-induced proapoptotic signaling R-HSA-5357905 Regulation of TNFR1 signaling R-HSA-5357956 TNFR1-induced NFkappaB signaling pathway R-HSA-5626978 TNFR1-mediated ceramide production R-HSA-5668541 TNFR2 non-canonical NF-kB pathway R-HSA-6783783 Interleukin-10 signaling R-HSA-6785807 Interleukin-4 and 13 signaling R-HSA-75893 TNF signaling
SIGNORⁱ	P01375

Reactomeⁱ

R-HSA-381340 Transcriptional regulation of white adipocyte differentiation
R-HSA-5357786 TNFR1-induced proapoptotic signaling
R-HSA-5357905 Regulation of TNFR1 signaling
R-HSA-5357956 TNFR1-induced NFkappaB signaling pathway
R-HSA-5626978 TNFR1-mediated ceramide production
R-HSA-5668541 TNFR2 non-canonical NF-kB pathway
R-HSA-6783783 Interleukin-10 signaling
R-HSA-6785807 Interleukin-4 and 13 signaling
R-HSA-75893 TNF signaling

SIGNORⁱ

P01375

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: Tumor necrosis factor, membrane form Alternative name(s): N-terminal fragment Short name: NTF Intracellular domain 1 Short name: ICD1 Intracellular domain 2 Short name: ICD2 C-domain 1 C-domain 2 Tumor necrosis factor, soluble form
Gene namesⁱ	Name:TNF Synonyms:TNFA, TNFSF2
Organismⁱ	Homo sapiens (Human)
Taxonomic identifierⁱ	9606 [NCBI]
Taxonomic lineageⁱ	cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Dipnotetrapodomorpha › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Boreoeutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo
Proteomesⁱ	UP000005640 Componentⁱ: Chromosome 6

Organism-specific databases

EuPathDBⁱ	HostDB:ENSG00000232810.3
Human Gene Nomenclature Database More...HGNCⁱ	HGNC:11892 TNF
MIMⁱ	191160 gene
neXtProtⁱ	NX_P01375

Topology

Feature key	Position(s)	DescriptionActions	Length
Topological domainⁱ	1 – 35	CytoplasmicSequence analysisAdd BLAST	35
Transmembraneⁱ	36 – 56	Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST	21
Topological domainⁱ	57 – 233	ExtracellularSequence analysisAdd BLAST	177

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).

Mutagenesis

Feature key	Position(s)	DescriptionActions	Length
Mutagenesisⁱ	105	L → S: Low activity. 1 Publication	1
Mutagenesisⁱ	108	R → W: Biologically inactive. 1 Publication	1
Mutagenesisⁱ	112	L → F: Biologically inactive. 1 Publication	1
Mutagenesisⁱ	160	A → V: Biologically inactive. 1 Publication	1
Mutagenesisⁱ	162	S → F: Biologically inactive. 1 Publication	1
Mutagenesisⁱ	167	V → A or D: Biologically inactive. 1 Publication	1
Mutagenesisⁱ	222	E → K: Biologically inactive. 1 Publication	1

Organism-specific databases

DisGeNET More...DisGeNETⁱ	7124
MalaCards human disease database More...MalaCardsⁱ	TNF
MIMⁱ	607507 phenotype 610424 phenotype 611162 phenotype
Open Targets More...OpenTargetsⁱ	ENSG00000232810
Orphanetⁱ	40050 Adult psoriatic arthritis
PharmGKBⁱ	PA435

Chemistry databases

ChEMBLⁱ	CHEMBL1825
Drug and drug target database More...DrugBankⁱ	DB05250 681323 DB00051 Adalimumab DB04956 Afelimomab DB05879 AME-527 DB01427 Amrinone DB05676 Apremilast DB05066 AV411 DB08904 Certolizumab pegol DB00608 Chloroquine DB01407 Clenbuterol DB05744 CRx-139 DB05869 CTI-01 DB05758 CYT007-TNFQb DB00668 Epinephrine DB00005 Etanercept DB01296 Glucosamine DB06674 Golimumab DB05767 HMPL-004 DB00065 Infliximab DB02325 Isopropyl Alcohol DB05303 OMS-103HP DB05218 PN0621 DB08910 Pomalidomide DB01411 Pranlukast DB00852 Pseudoephedrine DB05412 SCIO-469 DB05207 SD118 DB01041 Thalidomide DB05470 VX-702 DB05017 YSIL6

ChEMBLⁱ

CHEMBL1825

DrugBankⁱ

DB05250 681323
DB00051 Adalimumab
DB04956 Afelimomab
DB05879 AME-527
DB01427 Amrinone
DB05676 Apremilast
DB05066 AV411
DB08904 Certolizumab pegol
DB00608 Chloroquine
DB01407 Clenbuterol
DB05744 CRx-139
DB05869 CTI-01
DB05758 CYT007-TNFQb
DB00668 Epinephrine
DB00005 Etanercept
DB01296 Glucosamine
DB06674 Golimumab
DB05767 HMPL-004
DB00065 Infliximab
DB02325 Isopropyl Alcohol
DB05303 OMS-103HP
DB05218 PN0621
DB08910 Pomalidomide
DB01411 Pranlukast
DB00852 Pseudoephedrine
DB05412 SCIO-469
DB05207 SD118
DB01041 Thalidomide
DB05470 VX-702
DB05017 YSIL6

Polymorphism and mutation databases

BioMutaⁱ	TNF
DMDMⁱ	135934

PTM / Processingⁱ

Molecule processing

Feature key	Position(s)	DescriptionActions	Length
ChainⁱPRO_0000034423	1 – 233	Tumor necrosis factor, membrane formAdd BLAST	233
ChainⁱPRO_0000417231	1 – 39	Intracellular domain 1Add BLAST	39
ChainⁱPRO_0000417232	1 – 35	Intracellular domain 2Add BLAST	35
ChainⁱPRO_0000417233	50 – ?	C-domain 1
ChainⁱPRO_0000417234	52 – ?	C-domain 2
ChainⁱPRO_0000034424	77 – 233	Tumor necrosis factor, soluble form1 PublicationAdd BLAST	157

Amino acid modifications

Feature key	Position(s)	DescriptionActions	Length
Modified residueⁱ	2	Phosphoserine; by CK1Curated	1
Lipidationⁱ	19	N6-myristoyl lysine1 Publication	1
Lipidationⁱ	20	N6-myristoyl lysine1 Publication	1
Glycosylationⁱ	80	O-linked (GalNAc...) serine; in soluble form1 Publication	1
Disulfide bondⁱ	145 ↔ 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

Sites

Feature key	Position(s)	DescriptionActions	Length
Siteⁱ	35 – 36	Cleavage; by SPPL2A or SPPL2B	2
Siteⁱ	39 – 40	Cleavage; by SPPL2A or SPPL2B	2
Siteⁱ	49 – 50	Cleavage; by SPPL2A or SPPL2B	2
Siteⁱ	51 – 52	Cleavage; by SPPL2A or SPPL2B	2
Siteⁱ	76 – 77	Cleavage; by ADAM17	2

Keywords - PTMⁱ

Disulfide bond, Glycoprotein, Lipoprotein, Myristate, Phosphoprotein

Proteomic databases

PaxDbⁱ	P01375
PeptideAtlas More...PeptideAtlasⁱ	P01375
PRIDEⁱ	P01375
ProteomicsDBⁱ	12707 51379

PTM databases

GlyConnectⁱ	609
iPTMnetⁱ	P01375
PhosphoSitePlusⁱ	P01375
SwissPalmⁱ	P01375
UniCarbKBⁱ	P01375

Miscellaneous databases

PMAP-CutDBⁱ	P01375

PMAP-CutDBⁱ

P01375

Expressionⁱ

Gene expression databases

Bgeeⁱ	ENSG00000232810
CleanExⁱ	HS_TNF
ExpressionAtlasⁱ	P01375 baseline and differential
Genevisibleⁱ	P01375 HS

Interactionⁱ

Subunit structureⁱ

Homotrimer. Interacts with SPPL2B.1 Publication

Binary interactionsⁱ

With	Entry	#Exp.	IntAct	Notes
itself		3	EBI-359977,EBI-359977
2L	Q9DHW0	2	EBI-359977,EBI-15810797	From Yaba-like disease virus.
Casp8	O89110	2	EBI-359977,EBI-851690	From Mus musculus.
crmE	Q8UYL3	3	EBI-359977,EBI-7539950	From Vaccinia virus.
Ikbkb	O88351	3	EBI-359977,EBI-447960	From Mus musculus.
IKBKG	Q9Y6K9	2	EBI-359977,EBI-81279
Ripk1	Q60855	3	EBI-359977,EBI-529119	From Mus musculus.
Tnfaip3	Q60769	2	EBI-359977,EBI-646595	From Mus musculus.
TNFRSF1A	P19438	15	EBI-359977,EBI-299451
Tnfrsf1a	P25118	3	EBI-359977,EBI-518014	From Mus musculus.
TNFRSF1B	P20333	2	EBI-359977,EBI-358983
Tradd	Q3U0V2	2	EBI-359977,EBI-1544032	From Mus musculus.

Show more details

GO - Molecular functionⁱ

cytokine activity
Source: BHF-UCL
Inferred from direct assayⁱ
- 10748004
identical protein binding
Source: BHF-UCL
Inferred from direct assayⁱ
- 14512626
protease binding
Source: BHF-UCL
Inferred from physical interactionⁱ
- 12777399
tumor necrosis factor receptor binding
Source: BHF-UCL
Inferred from direct assayⁱ
- 14512626

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridⁱ	112979, 103 interactors
CORUMⁱ	P01375
Database of interacting proteins More...DIPⁱ	DIP-2895N
IntActⁱ	P01375, 81 interactors
Molecular INTeraction database More...MINTⁱ	P01375
STRINGⁱ	9606.ENSP00000398698

Chemistry databases

BindingDBⁱ	P01375

BindingDBⁱ

P01375

Structureⁱ

Secondary structure

Legend: HelixTurnBeta strandPDB Structure known for this area

Show more details

Feature key	Position(s)	DescriptionActions	Length
Beta strandⁱ	89 – 94	Combined sources	6
Beta strandⁱ	96 – 98	Combined sources	3
Beta strandⁱ	99 – 101	Combined sources	3
Beta strandⁱ	104 – 106	Combined sources	3
Beta strandⁱ	108 – 110	Combined sources	3
Beta strandⁱ	112 – 114	Combined sources	3
Beta strandⁱ	118 – 120	Combined sources	3
Beta strandⁱ	123 – 125	Combined sources	3
Beta strandⁱ	128 – 143	Combined sources	16
Beta strandⁱ	146 – 148	Combined sources	3
Beta strandⁱ	152 – 159	Combined sources	8
Beta strandⁱ	161 – 163	Combined sources	3
Beta strandⁱ	166 – 174	Combined sources	9
Beta strandⁱ	177 – 179	Combined sources	3
Beta strandⁱ	182 – 185	Combined sources	4
Beta strandⁱ	189 – 202	Combined sources	14
Beta strandⁱ	207 – 213	Combined sources	7
Helixⁱ	215 – 217	Combined sources	3
Beta strandⁱ	221 – 223	Combined sources	3
Beta strandⁱ	225 – 232	Combined sources	8

3D structure databases

ProteinModelPortalⁱ	P01375
SMRⁱ	P01375
ModBaseⁱ	Search...
MobiDBⁱ	Search...

Miscellaneous databases

EvolutionaryTraceⁱ	P01375

EvolutionaryTraceⁱ

P01375

Family & Domainsⁱ

Sequence similaritiesⁱ

Belongs to the tumor necrosis factor family.Curated

Keywords - Domainⁱ

Signal-anchor, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGⁱ	ENOG410ISAN Eukaryota ENOG410YQC4 LUCA
Ensembl GeneTree More...GeneTreeⁱ	ENSGT00530000062992
HOGENOMⁱ	HOG000048729
HOVERGENⁱ	HBG012516
InParanoidⁱ	P01375
KEGG Orthology (KO) More...KOⁱ	K03156
OMAⁱ	PWYEPIY
Database of Orthologous Groups More...OrthoDBⁱ	EOG091G0HIG
PhylomeDBⁱ	P01375
TreeFamⁱ	TF332169

Family and domain databases

Gene3Dⁱ	2.60.120.40, 1 hit
InterProⁱ	View protein in InterPro IPR006053 TNF IPR002959 TNF_alpha IPR021184 TNF_CS IPR006052 TNF_dom IPR008983 Tumour_necrosis_fac-like_dom
PANTHERⁱ	PTHR11471:SF23 PTHR11471:SF23, 1 hit
Pfam protein domain database More...Pfamⁱ	View protein in Pfam PF00229 TNF, 1 hit
PRINTSⁱ	PR01234 TNECROSISFCT PR01235 TNFALPHA
SMARTⁱ	View protein in SMART SM00207 TNF, 1 hit
SUPFAMⁱ	SSF49842 SSF49842, 1 hit
PROSITEⁱ	View protein in PROSITE PS00251 TNF_1, 1 hit PS50049 TNF_2, 1 hit

Sequenceⁱ

Sequence statusⁱ: Complete.

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

P01375-1 [UniParc]FASTA Add to basket

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        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

Sequence cautionⁱ

The sequence AAF71992 differs from that shown. Reason: Frameshift at positions 91 and 157.Curated

The sequence CAA75070 differs from that shown. Reason: Erroneous gene model prediction.Curated

Experimental Info

Feature key	Position(s)	DescriptionActions	Length
Sequence conflictⁱ	63	F → S in AAA61198 (PubMed:3856324).Curated	1
Sequence conflictⁱ	84 – 86	PSD → VNR in AAF71992 (Ref. 17) Curated	3
Sequence conflictⁱ	183	E → R in AAC03542 (Ref. 16) Curated	1

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 key	Position(s)	DescriptionActions	Graphical view	Length
Natural variantⁱVAR_019378	84	P → L1 PublicationCorresponds to variant dbSNP:rs4645843Ensembl.		1
Natural variantⁱVAR_011927	94	A → T. Corresponds to variant dbSNP:rs1800620Ensembl.		1

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.
The Consensus CDS (CCDS) project More...CCDSⁱ	CCDS4702.1
PIRⁱ	A93585 QWHUN
NCBI Reference Sequences More...RefSeqⁱ	NP_000585.2, NM_000594.3
UniGeneⁱ	Hs.241570

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

Keywords - Coding sequence diversityⁱ

Polymorphism

Similar proteinsⁱ

100% Identity
90% Identity
50% Identity

Protein	Similar proteins		Species	Score	Length
P01375	Tumor necrosis factor-alpha		HUMAN		233
TNF isoform 1		PANTR		233
Tumor necrosis factor		PANPA		233
Tumor necrosis factor		GORGO		233
Tumor necrosis factor alpha (Fragment)		AOTNA		149
+5

Protein	Similar proteins		Species	Score	Length
P01375	Tumor necrosis factor-alpha		HUMAN		233
TNF isoform 1		PANTR		233
Tumor necrosis factor		PANPA		233
Tumor necrosis factor		GORGO		233
Tumor necrosis factor alpha (Fragment)		AOTNA		149
+34

Protein	Similar proteins		Species	Score	Length
P01375	Tumor necrosis factor-alpha		HUMAN		233
TNF isoform 1		PANTR		233
Tumor necrosis factor		PANPA		233
Tumor necrosis factor		GORGO		233
Tumor necrosis factor alpha (Fragment)		AOTNA		149
+256

Select the link destinations: Protein Data Bank Europe More...PDBeⁱ Protein Data Bank RCSB More...RCSB PDBⁱ Protein Data Bank Japan More...PDBjⁱ Links Updated	PDB 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	[»]
4TWT	X-ray	2.85	A/B/C/D	77-233	[»]
4Y6O	X-ray	1.60	C/D	17-23	[»]
5M2I	X-ray	2.15	A/B/C/D/E/F	77-233	[»]
5M2J	X-ray	1.90	A	77-233	[»]
5M2M	X-ray	2.30	A/B/C/G/I/M	77-233	[»]
5MU8	X-ray	3.00	A/B/C/D/F/G/H/I/J/K/L/M/N/O/P/Q/R/S/T/U/V/W/X/Y/Z/a/b/c/d/e	77-233	[»]
5TSW	X-ray	2.50	A/B/C/D/E/F	84-233	[»]
5UUI	X-ray	1.40	A	77-233	[»]
5WUX	X-ray	2.90	E/F/G	77-233	[»]
5YOY	X-ray	2.73	A/B/C/J/K/L	76-233	[»]
ProteinModelPortalⁱ	P01375
SMRⁱ	P01375
ModBaseⁱ	Search...
MobiDBⁱ	Search...

BindingDBⁱ	P01375
ChEMBLⁱ	CHEMBL1825
Drug and drug target database More...DrugBankⁱ	DB05250 681323 DB00051 Adalimumab DB04956 Afelimomab DB05879 AME-527 DB01427 Amrinone DB05676 Apremilast DB05066 AV411 DB08904 Certolizumab pegol DB00608 Chloroquine DB01407 Clenbuterol DB05744 CRx-139 DB05869 CTI-01 DB05758 CYT007-TNFQb DB00668 Epinephrine DB00005 Etanercept DB01296 Glucosamine DB06674 Golimumab DB05767 HMPL-004 DB00065 Infliximab DB02325 Isopropyl Alcohol DB05303 OMS-103HP DB05218 PN0621 DB08910 Pomalidomide DB01411 Pranlukast DB00852 Pseudoephedrine DB05412 SCIO-469 DB05207 SD118 DB01041 Thalidomide DB05470 VX-702 DB05017 YSIL6

The DNASU plasmid repository More...DNASUⁱ	7124
Structural Biology Knowledgebase	Search...

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

CTDⁱ	7124
DisGeNET More...DisGeNETⁱ	7124
EuPathDBⁱ	HostDB:ENSG00000232810.3
GeneCardsⁱ	TNF
H-InvDBⁱ	HIX0165948
Human Gene Nomenclature Database More...HGNCⁱ	HGNC:11892 TNF
MalaCards human disease database More...MalaCardsⁱ	TNF
MIMⁱ	191160 gene 607507 phenotype 610424 phenotype 611162 phenotype
neXtProtⁱ	NX_P01375
Open Targets More...OpenTargetsⁱ	ENSG00000232810
Orphanetⁱ	40050 Adult psoriatic arthritis
PharmGKBⁱ	PA435
GenAtlas: human gene database More...GenAtlasⁱ	Search...

Reactomeⁱ	R-HSA-381340 Transcriptional regulation of white adipocyte differentiation R-HSA-5357786 TNFR1-induced proapoptotic signaling R-HSA-5357905 Regulation of TNFR1 signaling R-HSA-5357956 TNFR1-induced NFkappaB signaling pathway R-HSA-5626978 TNFR1-mediated ceramide production R-HSA-5668541 TNFR2 non-canonical NF-kB pathway R-HSA-6783783 Interleukin-10 signaling R-HSA-6785807 Interleukin-4 and 13 signaling R-HSA-75893 TNF signaling
SIGNORⁱ	P01375

ChiTaRSⁱ	TNF human
EvolutionaryTraceⁱ	P01375
GeneWikiⁱ	Tumor_necrosis_factor-alpha
GenomeRNAiⁱ	7124
PMAP-CutDBⁱ	P01375
Protein Ontology More...PROⁱ	PR:P01375
SOURCEⁱ	Search...

Entry informationⁱ

Entry nameⁱ	TNFA_HUMAN
Accessionⁱ	P01375Primary (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:	July 18, 2018
	This is version 238 of the entry and version 1 of the sequence. See complete history.
Entry statusⁱ	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.

Miscellaneousⁱ

Keywords - Technical termⁱ

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

Documents

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

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UniProtKB - P01375 (TNFA_HUMAN)

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Tumor necrosis factor

TNF

Select a section on the left to see content.

<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More...</a></p>Functioni

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<p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More...</a></p>Pathology & Biotechi

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<p>This section describes post-translational modifications (PTMs) and/or processing events.<p><a href='/help/ptm_processing_section' target='_top'>More...</a></p>PTM / Processingi

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<p>This section provides information on the quaternary structure of a protein and on interaction(s) with other proteins or protein complexes.<p><a href='/help/interaction_section' target='_top'>More...</a></p>Interactioni

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<p>This subsection of the ‘Sequence’ section reports difference(s) between the protein sequence shown in the UniProtKB entry and other available protein sequences derived from the same gene.<p><a href='/help/sequence_caution' target='_top'>More...</a></p>Sequence cautioni

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<p>This section is used to point to information related to entries and found in data collections other than UniProtKB.<p><a href='/help/cross_references_section' target='_top'>More...</a></p>Cross-referencesi

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Functionⁱ

GO - Molecular functionⁱ

GO - Biological processⁱ

Names & Taxonomyⁱ

Subcellular locationⁱ

Pathology & Biotechⁱ

PTM / Processingⁱ

Expressionⁱ

Interactionⁱ

GO - Molecular functionⁱ

Structureⁱ

Family & Domainsⁱ

Sequence similaritiesⁱ

Sequence cautionⁱ

Cross-referencesⁱ

Web resourcesⁱ

Entry informationⁱ

Miscellaneousⁱ