Letunic et al. (2017) Nucleic Acids Res doi: 10.1093/nar/gkx922
Letunic et al. (2020) Nucleic Acids Res doi: 10.1093/nar/gkaa937

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TNF Tumour necrosis factor family.

SMART accession number:	SM00207
Description:	Family of cytokines that form homotrimeric or heterotrimeric complexes. TNF mediates mature T-cell receptor-induced apoptosis through the p75 TNF receptor.
Interpro abstract (IPR006052):	Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities [ (PUBMED:8095800) (PUBMED:1377364) (PUBMED:15335677) ]. Tumor necrosis factor (TNF) (also known as TNF-alpha or cachectin) is a monocyte-derived cytotoxin that has been implicated in tumour regression, septic shock and cachexia [ (PUBMED:2989794) (PUBMED:3349526) ]. The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine [ (PUBMED:2268312) ]. A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers [ (PUBMED:2777790) ]. Both the mature protein and a partially-processed form of the hormone are secreted after cleavage of the propeptide [ (PUBMED:2777790) ]. There are a number of different families of TNF, but all these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors. The following cytokines can be grouped into a family on the basis of sequence, functional, and structural similarities [ (PUBMED:8095800) (PUBMED:1377364) (PUBMED:15335677) ]: Tumor Necrosis Factor (TNF) (also known as cachectin or TNF-alpha) [ (PUBMED:3061461) (PUBMED:1850405) ] is a cytokine which has a wide variety of functions. It can cause cytolysis of certain tumor cell lines; it is involved in the induction of cachexia; it is a potent pyrogen, causing fever by direct action or by stimulation of interleukin-1 secretion; finally, it can stimulate cell proliferation and induce cell differentiation under certain conditions. Lymphotoxin-alpha (LT-alpha) and lymphotoxin-beta (LT-beta), two related cytokines produced by lymphocytes and which are cytotoxic for a wide range of tumor cells in vitro and in vivo [ (PUBMED:7916655) ]. T cell antigen gp39 (CD40L), a cytokine which seems to be important in B-cell development and activation. CD27L, a cytokine which plays a role in T-cell activation. It induces the proliferation of costimulated T cells and enhances the generation of cytolytic T cells. CD30L, a cytokine which induces proliferation of T cells. FASL, a cytokine involved in cell death [ (PUBMED:7505205) ]. 4-1BBL, a inducible T cell surface molecule that contributes to T-cell stimulation. OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production [ (PUBMED:8076595) ]. TNF-related apoptosis inducing ligand (TRAIL), a cytokine that induces apoptosis [ (PUBMED:8777713) ]. TNF-alpha is synthesised as a type II membrane protein which then undergoes post-translational cleavage liberating the extracellular domain. CD27L, CD30L, CD40L, FASL, LT-beta, 4-1BBL and TRAIL also appear to be type II membrane proteins. LT-alpha is a secreted protein. All these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognised by their specific receptors. The PROSITE pattern for this family is located in a beta-strand in the central section of the protein which is conserved across all members.
GO process:	immune response (GO:0006955)
GO component:	membrane (GO:0016020)
GO function:	tumor necrosis factor receptor binding (GO:0005164)
Family alignment:	View or CHROMA formatHMM/Web logoCLUSTALW formatMSF formatFASTA formatPIR format

There are 5212 TNF domains in 5186 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Taxonomic distribution of proteins containing TNF domain.

  This tree includes only several representative species. The complete taxonomic breakdown of all proteins with TNF domain is also avaliable.

  Click on the protein counts, or double click on taxonomic names to display all proteins containing TNF domain in the selected taxonomic class.

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Zheng L, Fisher G, Miller RE, Peschon J, Lynch DH, Lenardo MJ
  • Induction of apoptosis in mature T cells by tumour necrosis factor.
  • Nature. 1995; 377: 348-51
  • Display abstract

  • T-cell receptor-induced apoptosis regulates immune responses and can result from interactions between Fas (Apo1/CD95) and Fas ligand (FasL). Mutations in the genes for Fas and FasL cause disorders resembling human autoimmune diseases in lpr and gld mice, respectively. However, peripheral T-cell deletion takes place in lpr mice, and autoimmune syndromes occur in mouse strains without Fas or FasL defects. Here we show that tumour necrosis factor (TNF) can mediate mature T-cell receptor-induced apoptosis through the p75 TNF receptor. Blockage of both TNF and FasL is required to abrogate T-cell death and TNF mediates the death of most CD8+ T cells, whereas FasL mediates the death of most CD4+ T cells. Our results suggest that autoregulatory apoptosis of the mature T cells can occur by two distinct molecular mechanisms.

  • Armitage RJ
  • Tumor necrosis factor receptor superfamily members and their ligands.
  • Curr Opin Immunol. 1994; 6: 407-13
  • Display abstract

  • The tumor necrosis factor (TNF) receptor family comprises a number of type I integral membrane glycoproteins which exhibit sequence homology in their cysteine-rich extracellular domains. Recently, ligands for many of these receptors have been identified. These molecules all display sequence identity with TNF and lymphotoxin beta, prototype ligands for this receptor family, and have the conformation of type II transmembrane molecules. While certain biological activities are common to many members of this TNF-like family, other activities appear to be shared only by some ligands, or are unique. The identification of the TNF superfamily of ligands has provided the opportunity to compare and contrast the diverse biological effects mediated through the interaction of these related molecules with their receptors.

  • Beutler B, VanHuffel C
  • An evolutionary and functional approach to the TNF receptor/ligand family.
  • Ann N Y Acad Sci. 1994; 730: 118-33

  • Beyaert R, Fiers W
  • Molecular mechanisms of tumor necrosis factor-induced cytotoxicity. What we do understand and what we do not.
  • FEBS Lett. 1994; 340: 9-16
  • Display abstract

  • Although TNF plays an important role in several physiological and pathological conditions, the hallmark of this important cytokine has been its selective cytotoxic activity on tumor cells. Since its cloning in 1984, understanding of how TNF selectively kills tumor cells has been the subject of research in many laboratories. Here we review TNF-induced post-receptor signaling mechanisms which seem to be involved in the pathway to cytotoxicity.

  • Takahashi T et al.
  • Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand.
  • Cell. 1994; 76: 969-76
  • Display abstract

  • Mice homozygous for lpr (lymphoproliferation) or gld (generalized lymphoproliferative disease) develop lymphadenopathy and suffer from autoimmune disease. The lpr mice have a mutation in a cell-surface protein, Fas, that mediates apoptosis. Fas ligand (FasL) is a tumor necrosis factor (TNF)-related type II membrane protein and binds to Fas. Here, mouse Fasl gene was isolated and localized to the gld region of mouse chromosome 1. Activated splenocytes from gld mice express Fasl mRNA. However, FasL in gld mice carries a point mutation in the C-terminal region, which is highly conserved among members of the TNF family. The recombinant gld FasL expressed in COS cells could not induce apoptosis in cells expressing Fas. These results indicate that lpr and gld are mutations in Fas and Fasl, respectively, and suggest important roles of the Fas system in development of T cells as well as cytotoxic T lymphocyte-mediated cytotoxicity.

  • Tartaglia LA, Rothe M, Hu YF, Goeddel DV
  • Tumor necrosis factor's cytotoxic activity is signaled by the p55 TNF receptor.
  • Cell. 1993; 73: 213-6

  • Vassalli P
  • The pathophysiology of tumor necrosis factors.
  • Annu Rev Immunol. 1992; 10: 411-52
• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the TNF domain.

  Protein	Disease
  CD40 ligand (P29965) (SMART)	OMIM:308230: Immunodeficiency, X-linked, with hyper-IgM

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 38.04 map04060 Cytokine-cytokine receptor interaction 8.70 map04210 Apoptosis 8.70 map04650 Natural killer cell mediated cytotoxicity 8.33 map04940 Type I diabetes mellitus 5.80 map04010 MAPK signaling pathway 5.07 map04660 T cell receptor signaling pathway 2.54 map04640 Hematopoietic cell lineage 2.54 map04664 Fc epsilon RI signaling pathway 2.54 map05060 Prion disease 2.54 map04350 TGF-beta signaling pathway 2.54 map04620 Toll-like receptor signaling pathway 2.54 map04612 Antigen processing and presentation 2.54 map04930 Type II diabetes mellitus 2.54 map05010 Alzheimer's disease 2.54 map04920 Adipocytokine signaling pathway 2.54 map04514 Cell adhesion molecules (CAMs) This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with TNF domain which could be assigned to a KEGG orthologous group, and not all proteins containing TNF domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of TNF domains in PDB

  PDB code	Main view	Title
  1a8m		TUMOR NECROSIS FACTOR ALPHA, R31D MUTANT
  1aly		CRYSTAL STRUCTURE OF HUMAN CD40 LIGAND
  1d0g		CRYSTAL STRUCTURE OF DEATH RECEPTOR 5 (DR5) BOUND TO APO2L/TRAIL
  1d2q		CRYSTAL STRUCTURE OF HUMAN TRAIL
  1d4v		Crystal structure of trail-DR5 complex
  1dg6		CRYSTAL STRUCTURE OF APO2L/TRAIL
  1du3		Crystal structure of TRAIL-SDR5
  1i9r		STRUCTURE OF CD40L IN COMPLEX WITH THE FAB FRAGMENT OF HUMANIZED 5C8 ANTIBODY
  1iqa		CRYSTAL STRUCTURE OF THE EXTRACELLULAR DOMAIN OF MOUSE RANK LIGAND
  1jh5		Crystal Structure of sTALL-1 of TNF family ligand
  1jtz		CRYSTAL STRUCTURE OF TRANCE/RANKL CYTOKINE.
  1kd7		Crystal structure of an extracellular domain fragment of human BAFF
  1kxg		The 2.0 Ang Resolution Structure of BLyS, B Lymphocyte Stimulator.
  1oqd		Crystal structure of sTALL-1 and BCMA
  1oqe		Crystal structure of sTALL-1 with BAFF-R
  1osg		Complex between BAFF and a BR3 derived peptide presented in a beta-hairpin scaffold
  1rj7		Crystal structure of EDA-A1
  1rj8		The crystal structure of TNF family member EDA-A2
  1s55		Mouse RANKL Structure at 1.9A Resolution
  1tnf		THE STRUCTURE OF TUMOR NECROSIS FACTOR-ALPHA AT 2.6 ANGSTROMS RESOLUTION. IMPLICATIONS FOR RECEPTOR BINDING
  1tnr		CRYSTAL STRUCTURE OF THE SOLUBLE HUMAN 55 KD TNF RECEPTOR-HUMAN TNF-BETA COMPLEX: IMPLICATIONS FOR TNF RECEPTOR ACTIVATION
  1u5x		Crystal structure of murine APRIL at pH 5.0
  1u5y		Crystal structure of murine APRIL, pH 8.0
  1u5z		The Crystal structure of murine APRIL, pH 8.5
  1xu1		The crystal structure of APRIL bound to TACI
  1xu2		The crystal structure of APRIL bound to BCMA
  2az5		Crystal Structure of TNF-alpha with a small molecule inhibitor
  2e7a		TNF Receptor Subtype One-selective TNF Mutant with Antagonistic Activity
  2hev		Crystal structure of the complex between OX40L and OX40
  2hew		The X-ray crystal structure of murine OX40L
  2hey		Crystal structure of murine OX40L bound to human OX40
  2o0o		Crystal structure of TL1A
  2qe3		Crystal structure of human tl1a extracellular domain
  2re9		Crystal structure of TL1A at 2.1 A
  2rjk		Crystal Structure of Human TL1A Extracellular Domain C95S Mutant
  2rjl		Crystal structure of human TL1A extracellular domain C95S/C135S mutant
  2tnf		1.4 A RESOLUTION STRUCTURE OF MOUSE TUMOR NECROSIS FACTOR, TOWARDS MODULATION OF ITS SELCTIVITY AND TRIMERISATION
  2tun		CONFORMATIONAL CHANGES IN THE (ALA-84-VAL) MUTANT OF TUMOR NECROSIS FACTOR
  2x29		Crystal structure of human4-1BB ligand ectodomain
  2zjc		TNFR1 selectve TNF mutant; R1-6
  2zpx		TNF Receptor Subtype One-selective TNF Mutant with Antagonistic Activity; R1antTNF-T8
  3alq		Crystal structure of TNF-TNFR2 complex
  3it8		Crystal structure of TNF alpha complexed with a poxvirus MHC-related TNF binding protein
  3k48		Crystal structure of APRIL bound to a peptide
  3k51		Crystal Structure of DcR3-TL1A complex
  3l9j		Selection of a novel highly specific TNFalpha antagonist: Insight from the crystal structure of the antagonist-TNFalpha complex
  3lkj		Small Molecule Inhibition of the TNF Family Cyokine CD40 Ligand Through a Subunit Fracture Mechanism
  3me2		Crystal structure of mouse RANKL-RANK complex
  3mi8		The structure of TL1A-DCR3 COMPLEX
  3qbq		Crystal structure of extracellular domains of mouse RANK-RANKL complex
  3qd6		Crystal structure of the CD40 and CD154 (CD40L) complex
  3urf		Human RANKL/OPG complex
  3v56		Re-refinement of PDB entry 1OSG - Complex between BAFF and a BR3 derived peptide presented in a beta-hairpin scaffold - reveals an additonal copy of the peptide.
  3wd5		Crystal structure of TNFalpha in complex with Adalimumab Fab fragment
  4e4d		Crystal structure of mouse RANKL-OPG complex
  4e4s		Crystal structure of Pika GITRL
  4en0		Crystal structure of light
  4g3y		Crystal structure of TNF-alpha in complex with Infliximab Fab fragment
  4giq		Crystal Structure of mouse RANK bound to RANKL
  4ht1		Human TWEAK in complex with the Fab fragment of a neutralizing antibody
  4j6g		CRYSTAL STRUCTURE OF LIGHT AND DcR3 COMPLEX
  4kg8		Crystal structure of light mutant
  4kgg		Crystal structure of light mutant2 and dcr3 complex
  4kgq		Crystal structure of a human light loop mutant in complex with dcr3
  4msv		Crystal structure of FASL and DcR3 complex
  4mxv		Structure of Lymphotoxin alpha bound to anti-LTa Fab
  4mxw		Structure of heterotrimeric lymphotoxin LTa1b2 bound to lymphotoxin beta receptor LTbR and anti-LTa Fab
  4n90		4N90
  4rsu		4RSU
  4tsv		HIGH RESOLUTION CRYSTAL STRUCTURE OF A HUMAN TNF-ALPHA MUTANT
  4twt		4TWT
  4v46		4V46
  4zch		4ZCH
  5bnq		5BNQ
  5l19		5L19
  5l36		5L36
  5tsw		HIGH RESOLUTION CRYSTAL STRUCTURE OF A HUMAN TNF-ALPHA MUTANT

• Links (links to other resources describing this domain)

• PROSITE	TNF_DOMAIN
  PFAM	TNF
  INTERPRO	IPR006052

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