Q06599 (TNFA_BOVIN) 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

Bos taurus (Bovine) [Reference proteome]

Taxonomic identifier

9913 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Laurasiatheria › Cetartiodactyla › Ruminantia › Pecora › Bovidae › Bovinae › Bos

Protein attributes

Sequence length	234 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at transcript 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. The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells By similarity.
Subunit structure	Homotrimer. Interacts with SPPL2B By similarity.
Subcellular location	Cell membrane; Single-pass type II membrane protein By similarity. Tumor necrosis factor, membrane form: Membrane; Single-pass type II membrane protein By similarity. Tumor necrosis factor, soluble form: Secreted By similarity. C-domain 1: Secreted By similarity. C-domain 2: Secreted By similarity.
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 By similarity. 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 By similarity. O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid By similarity.
Sequence similarities	Belongs to the tumor necrosis factor family.
Sequence caution	The sequence AAA19573.1 differs from that shown. Reason: Erroneous gene model prediction.

Ontologies

Keywords
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Signal-anchor Transmembrane Transmembrane helix
Molecular function	Cytokine
PTM	Disulfide bond Glycoprotein Lipoprotein Myristate Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	JNK cascade Inferred from electronic annotation. Source: Compara activation of MAPK activity Inferred from electronic annotation. Source: Compara activation of MAPKKK activity Inferred from electronic annotation. Source: Compara activation of cysteine-type endopeptidase activity involved in apoptotic process Inferred from electronic annotation. Source: Compara activation of necroptosis by extracellular signals Inferred from electronic annotation. Source: Compara cellular response to amino acid stimulus Inferred from electronic annotation. Source: Compara cellular response to nicotine Inferred from electronic annotation. Source: Compara chronic inflammatory response to antigenic stimulus Inferred from electronic annotation. Source: Compara defense response to Gram-positive bacterium Inferred from electronic annotation. Source: Compara embryonic digestive tract development Inferred from electronic annotation. Source: Compara 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 electronic annotation. Source: Compara glucose metabolic process Inferred from electronic annotation. Source: Compara humoral immune response Inferred from electronic annotation. Source: Compara induction of apoptosis Inferred from electronic annotation. Source: Compara leukocyte tethering or rolling Inferred from electronic annotation. Source: Compara lipopolysaccharide-mediated signaling pathway Inferred from electronic annotation. Source: Compara necrotic cell death 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 electronic annotation. Source: Compara negative regulation of branching involved in lung morphogenesis Inferred from electronic annotation. Source: Compara negative regulation of cytokine secretion involved in immune response Inferred from electronic annotation. Source: Compara 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 electronic annotation. Source: Compara negative regulation of lipid catabolic process Inferred from electronic annotation. Source: Compara negative regulation of osteoblast differentiation Inferred from electronic annotation. Source: Compara negative regulation of protein complex disassembly Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara negative regulation of viral genome replication Inferred from electronic annotation. Source: Compara organ morphogenesis Inferred from electronic annotation. Source: Compara osteoclast differentiation Inferred from electronic annotation. Source: Compara positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from electronic annotation. Source: Compara positive regulation of JNK cascade Inferred from electronic annotation. Source: Compara positive regulation of JUN kinase activity Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of NF-kappaB import into nucleus Inferred from electronic annotation. Source: Compara positive regulation of NF-kappaB transcription factor activity Inferred from electronic annotation. Source: Compara positive regulation of NFAT protein import into nucleus Inferred from electronic annotation. Source: Compara positive regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of calcidiol 1-monooxygenase activity Inferred from electronic annotation. Source: Compara positive regulation of chemokine (C-X-C motif) ligand 2 production Inferred from electronic annotation. Source: Compara positive regulation of chemokine biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of chronic inflammatory response to antigenic stimulus Inferred from electronic annotation. Source: Compara positive regulation of cytokine secretion Inferred from electronic annotation. Source: Compara positive regulation of fever generation Inferred from electronic annotation. Source: Compara positive regulation of hair follicle development Inferred from electronic annotation. Source: Compara positive regulation of heterotypic cell-cell adhesion Inferred from electronic annotation. Source: Compara 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 electronic annotation. Source: Compara positive regulation of membrane protein ectodomain proteolysis Inferred from electronic annotation. Source: Compara positive regulation of nitric oxide biosynthetic process Inferred from electronic annotation. Source: Compara positive regulation of osteoclast differentiation Inferred from electronic annotation. Source: Compara positive regulation of peptidyl-serine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of podosome assembly Inferred from electronic annotation. Source: Compara positive regulation of protein complex disassembly Inferred from sequence or structural similarity. 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 electronic annotation. Source: Compara positive regulation of smooth muscle cell proliferation Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara positive regulation of translational initiation by iron Inferred from electronic annotation. Source: Compara positive regulation of vitamin D biosynthetic process Inferred from electronic annotation. Source: Compara protein import into nucleus, translocation Inferred from electronic annotation. Source: Compara protein kinase B signaling cascade Inferred from electronic annotation. Source: Compara receptor biosynthetic process Inferred from electronic annotation. Source: Compara 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 electronic annotation. Source: Compara response to glucocorticoid stimulus Inferred from electronic annotation. Source: Compara response to virus Inferred from electronic annotation. Source: Compara sequestering of triglyceride Inferred from electronic annotation. Source: Compara transformed cell apoptotic process Inferred from electronic annotation. Source: Compara tumor necrosis factor-mediated signaling pathway Inferred from electronic annotation. Source: Compara
Cellular_component	external side of plasma membrane Inferred from electronic annotation. Source: Compara extracellular space Inferred from electronic annotation. Source: UniProtKB-KW integral to plasma membrane Inferred from electronic annotation. Source: Compara membrane raft Inferred from electronic annotation. Source: Compara phagocytic cup Inferred from electronic annotation. Source: Compara recycling endosome Inferred from electronic annotation. Source: Compara
Molecular_function	transcription regulatory region DNA binding Inferred from electronic annotation. Source: Compara
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q06599-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q06599-2)

The sequence of this isoform differs from the canonical sequence as follows:
     63-63: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 234	234	Tumor necrosis factor, membrane form		PRO_0000034403
	Chain	1 – 39	39	Intracellular domain 1 By similarity		PRO_0000417179
	Chain	1 – 35	35	Intracellular domain 2 By similarity		PRO_0000417180
	Chain	50 – ?		C-domain 1 By similarity		PRO_0000417181
	Chain	52 – ?		C-domain 2 By similarity		PRO_0000417182
	Chain	78 – 234	157	Tumor necrosis factor, soluble form		PRO_0000034404
Regions
	Topological domain	1 – 35	35	Cytoplasmic Potential
	Transmembrane	36 – 56	21	Helical; Signal-anchor for type II membrane protein; Potential
	Topological domain	57 – 234	178	Extracellular Potential
Sites
	Site	34 – 35	2	Cleavage; by SPPL2A or SPPL2B By similarity
	Site	39 – 40	2	Cleavage; by SPPL2A or SPPL2B By similarity
	Site	49 – 50	2	Cleavage; by SPPL2A or SPPL2B By similarity
	Site	51 – 52	2	Cleavage; by SPPL2A or SPPL2B By similarity
	Site	77 – 78	2	Cleavage; by ADAM17 By similarity
Amino acid modifications
	Modified residue	2	1	Phosphoserine; by CK1 By similarity
	Lipidation	20	1	N6-myristoyl lysine By similarity
	Glycosylation	81	1	O-linked (GalNAc...); in soluble form By similarity
	Disulfide bond	146 ↔ 178		By similarity
Natural variations
	Alternative sequence	63	1	Missing in isoform 2.		VSP_026198
	Natural variant	48	1	F → C in strain: N'Dama.
Experimental info
	Sequence conflict	114	1	M → V in AAN76506. Ref.3
	Sequence conflict	167	1	K → R in AAN76506. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified June 26, 2007. Version 2. Checksum: BAE4D0CD3797F491	FASTA	234	25,567
	10 20 30 40 50 60 MSTKSMIRDV ELAEEVLSEK AGGPQGSRSC LCLSLFSFLL VAGATTLFCL LHFGVIGPQR 70 80 90 100 110 120 EEQSPGGPSI NSPLVQTLRS SSQASSNKPV AHVVADINSP GQLRWWDSYA NALMANGVKL 130 140 150 160 170 180 EDNQLVVPAD GLYLIYSQVL FRGQGCPSTP LFLTHTISRI AVSYQTKVNI LSAIKSPCHR 190 200 210 220 230 ETPEWAEAKP WYEPIYQGGV FQLEKGDRLS AEINLPDYLD YAESGQVYFG IIAL
	Isoform 2 [UniParc]. Checksum: 8AF55C002A9763B0	FASTA	233	25,439
	10 20 30 40 50 60 MSTKSMIRDV ELAEEVLSEK AGGPQGSRSC LCLSLFSFLL VAGATTLFCL LHFGVIGPQR 70 80 90 100 110 120 EESPGGPSIN SPLVQTLRSS SQASSNKPVA HVVADINSPG QLRWWDSYAN ALMANGVKLE 130 140 150 160 170 180 DNQLVVPADG LYLIYSQVLF RGQGCPSTPL FLTHTISRIA VSYQTKVNIL SAIKSPCHRE 190 200 210 220 230 TPEWAEAKPW YEPIYQGGVF QLEKGDRLSA EINLPDYLDY AESGQVYFGI IAL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of the tandemly arranged bovine lymphotoxin and tumour necrosis factor-alpha genes." Cludts I., Cleuter Y., Kettmann R., Burny A., Droogmans L. Cytokine 5:336-341(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2).
[2]	"Bovine TNF-alpha gene." Iraqi F. Submitted (JUL-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2). Strain: Boran and N'Dama.
[3]	Ahn J. Submitted (FEB-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[4]	"U.S. veterinary immune reagent network: expressed bovine gene sequences." U.S. Veterinary Immune Reagent Network Hudgens T., Tompkins D., Baldwin C.L. Submitted (NOV-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Strain: Belted Galloway. Tissue: Peripheral blood.
[5]	NIH - Mammalian Gene Collection (MGC) project Submitted (MAR-2007) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Strain: Hereford. Tissue: Thymus.
[6]	"Cloning of two members of the TNF-superfamily in cattle: CD40 ligand and tumor necrosis factor alpha." Mertens B.E.L.C., Muriuki M., Gaidulis L. Immunogenetics 42:430-431(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 50-233 (ISOFORM 1). Tissue: Blood.
[7]	"Rapid communication: single strand conformational polymorphism (SSCP) of bovine tumor necrosis factor alpha." Dietz A.B., Neibergs H.L., Womack J.E., Kehrli M.E. Jr. J. Anim. Sci. 75:2567-2567(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 91-193. Strain: Holstein.

Cross-references

Sequence databases
EMBL GenBank DDBJ	Z14137 Genomic DNA. Translation: CAA78511.1. AF011926 Genomic DNA. Translation: AAB84086.1. AF011927 Genomic DNA. Translation: AAB84087.1. AF348421 mRNA. Translation: AAN76506.1. EU276079 mRNA. Translation: ABX72077.1. BC134755 mRNA. Translation: AAI34756.1. Z48808 mRNA. Translation: CAA88743.1. U11040 Genomic DNA. Translation: AAA19573.1. Sequence problems.
IPI	IPI00705704. IPI00852462.
PIR	S24642. I46047.
RefSeq	NP_776391.2. NM_173966.3.
UniGene	Bt.12756.
3D structure databases
ProteinModelPortal	Q06599.
SMR	Q06599. Positions 83-234.
ModBase	Search...
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSBTAT00000035815; ENSBTAP00000035682; ENSBTAG00000025471.
GeneID	280943.
KEGG	bta:280943.
Organism-specific databases
CTD	7124.
Phylogenomic databases
eggNOG	NOG40413.
GeneTree	ENSGT00530000062992.
HOGENOM	HOG000048729.
HOVERGEN	HBG012516.
InParanoid	Q06599.
KO	K03156.
OMA	WYEPIYL.
OrthoDB	EOG4JWVFT.
Gene expression databases
ArrayExpress	Q06599.
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
NextBio	20805057.

Entry information

Entry name

TNFA_BOVIN

Accession

Primary (citable) accession number: Q06599
Secondary accession number(s): A4IFT5 , A9QWR7, O18779, Q27978

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	June 26, 2007
Last modified:	May 1, 2013
This is version 112 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program