SMART: TNF domain annotation

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 recognized 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 synthesized 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 recognized 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

There are 549 TNF domains in 549 proteins in SMART's nrdb database.

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Evolution (species in which this domain is found)
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This tree shows only several representative species. The complete taxonomic breakdown of all proteins with TNF domain is also avaliable.

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Go to specific node: Anopheles gambiae, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Takifugu rubripes
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)

Metabolism (metabolic pathways involving proteins which contain this domain)

Structure (3D structures containing this domain)

Protein	Disease
CD40 ligand (CD40-L) (Tumor necrosis factor ligand superfamily member 5) (TNF-related activation protein) (TRAP) (T-cell antigen Gp39) (CD154 antigen) [Contains: CD40 ligand, membrane form; CD40 ligand, soluble form] (SRS)(SMART)	OMIM:308230: Immunodeficiency, X-linked, with hyper-IgM

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
1otz		Crystal structure of the baff-baff-r complex (part i)
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
2rjl
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
2zjc
2zpx
3it8
3k48
4tsv		High resolution crystal structure of a human tnf-alpha mutant
5tsw		High resolution crystal structure of a human tnf-alpha mutant

Links (links to other resources describing this domain)
BLOCKS TNF_1
PFAM TNF
INTERPRO IPR006052
PROSITE TNF_DOMAIN

BLOCKS	TNF_1
PFAM	TNF
INTERPRO	IPR006052
PROSITE	TNF_DOMAIN