| IED ID | IndEnz0002009711 |
| Enzyme Type ID | protease009711 |
| Protein Name |
Tumor necrosis factor Cachectin TNF-alpha Tumor necrosis factor ligand superfamily member 2 TNF-a Cleaved into: Tumor necrosis factor, membrane form N-terminal fragment NTF ; Intracellular domain 1 ICD1 ; Intracellular domain 2 ICD2 ; C-domain 1; C-domain 2; Tumor necrosis factor, soluble form |
| Gene Name | TNF TNFA TNFSF2 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MSTESMIRDVELAEEALPKKTGGPQGSRRCLFLSLFSFLIVAGATTLFCLLHFGVIGPQREEFPRDLSLISPLAQAVRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL |
| Enzyme Length | 233 |
| Uniprot Accession Number | P01375 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | |
| DNA Binding | |
| EC Number | |
| Enzyme Function | 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. Impairs regulatory T-cells (Treg) function in individuals with rheumatoid arthritis via FOXP3 dephosphorylation. Up-regulates 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, PubMed:16829952, PubMed:23396208). Induces insulin resistance in adipocytes via inhibition of insulin-induced IRS1 tyrosine phosphorylation and insulin-induced glucose uptake. Induces GKAP42 protein degradation in adipocytes which is partially responsible for TNF-induced insulin resistance (By similarity). Plays a role in angiogenesis by inducing VEGF production synergistically with IL1B and IL6 (PubMed:12794819). {ECO:0000250|UniProtKB:P06804, ECO:0000269|PubMed:12794819, ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:22517918, ECO:0000269|PubMed:23396208}.; FUNCTION: The TNF intracellular domain (ICD) form induces IL12 production in dendritic cells. {ECO:0000269|PubMed:16829952}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Beta strand (19); Chain (6); Disulfide bond (1); Erroneous gene model prediction (1); Frameshift (1); Glycosylation (1); Helix (1); Lipidation (2); Modified residue (1); Mutagenesis (7); Natural variant (2); Sequence conflict (3); Site (5); Topological domain (2); Transmembrane (1) |
| Keywords | 3D-structure;Cell membrane;Cytokine;Direct protein sequencing;Disulfide bond;Glycoprotein;Lipoprotein;Membrane;Myristate;Phosphoprotein;Reference proteome;Secreted;Signal-anchor;Transmembrane;Transmembrane helix |
| Interact With | P05067; Q92482; Q9BXK5; Q6UXG8-3; Q8IYJ2-2; Q8WV48; Q6NSX1; O95471; Q8IUN9; Q96BA8; P00387; Q5JX71; O15552; Q8TBE3; Q9Y6K9; Q8N6L0; Q8N386; O43300; Q9HC36; O75459; Q96RD7; Q8N4L2; Q53GL0; Q6ZMZ0; Q16585; Q15849; O14863; Q8WWF3; P27105; Q16623; O15393-2; Itself; P19438; P20333; Q9H7M9; Q6PEW1; Q9DHW0; O89110; Q8UYL3; O88351; Q60855; Q60769; P25118; Q3U0V2 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16829952}; Single-pass type II membrane protein {ECO:0000269|PubMed:16829952}.; SUBCELLULAR LOCATION: [Tumor necrosis factor, membrane form]: Membrane; Single-pass type II membrane protein.; SUBCELLULAR LOCATION: [Tumor necrosis factor, soluble form]: Secreted.; SUBCELLULAR LOCATION: [C-domain 1]: Secreted.; SUBCELLULAR LOCATION: [C-domain 2]: Secreted. |
| Modified Residue | MOD_RES 2; /note=Phosphoserine; by CK1; /evidence=ECO:0000305 |
| Post Translational Modification | PTM: 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. {ECO:0000269|PubMed:16829951, ECO:0000269|PubMed:16829952, ECO:0000269|PubMed:9034191}.; PTM: 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. {ECO:0000269|PubMed:10205166, ECO:0000269|PubMed:8597870}.; PTM: O-glycosylated; glycans contain galactose, N-acetylgalactosamine and N-acetylneuraminic acid. {ECO:0000269|PubMed:8631363}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (3); X-ray crystallography (36) |
| Cross Reference PDB | 1A8M; 1TNF; 2AZ5; 2E7A; 2TUN; 2ZJC; 2ZPX; 3ALQ; 3IT8; 3L9J; 3WD5; 4G3Y; 4TSV; 4TWT; 4Y6O; 5M2I; 5M2J; 5M2M; 5MU8; 5TSW; 5UUI; 5WUX; 5YOY; 6OOY; 6OOZ; 6OP0; 6RMJ; 6X81; 6X82; 6X83; 6X85; 6X86; 7ASY; 7AT7; 7ATB; 7JRA; 7KP9; 7KPA; 7KPB; |
| Mapped Pubmed ID | !!!TOLONGITDOESNOTFITINEXCELL,NOTREPRESENTABLEINEXCELL!!!; |
| Motif | |
| Gene Encoded By | |
| Mass | 25,644 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | |
| Cross Reference Brenda |