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271  structures 195  species 5  interactions 1178  sequences 10  architectures

Family: TNF (PF00229)

Summary: TNF(Tumour Necrosis Factor) family

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This is the Wikipedia entry entitled "Tumor necrosis factors". More...

Tumor necrosis factors Edit Wikipedia article

TNF(Tumor Necrosis Factor) family
Mouse Tumor Necrosis Factor Alpha.png
Trimeric structure of TNF alpha, produced by Mus musculus, based on PDB structure 2TNF (1.4 Å Resolution). Different colors represent different monomers. Baeyens, KJ et al. (1999).[1] Figure rendered using FirstGlance Jmol.
Identifiers
Symbol TNF
Pfam PF00229
InterPro IPR006052
PROSITE PDOC00224
SCOP 1tnf
SUPERFAMILY 1tnf
OPM superfamily 357
OPM protein 2hew
TNF
PDB 1du3 EBI.jpg
crystal structure of trail-sdr5
Identifiers
Symbol TNF
Pfam PF00229
Pfam clan CL0100
InterPro IPR006052
PROSITE PDOC00561
SCOP 1tnr
SUPERFAMILY 1tnr

Tumor necrosis factors (or the TNF family) refer to a group of cytokines that can cause cell death (apoptosis). The first two members of the family to be identified were:

  • Tumor necrosis factor (TNF), formerly known as TNFα or TNF alpha, is the best-known member of this class. TNF is a monocyte-derived cytotoxin that has been implicated in tumor regression, septic shock, and cachexia.[2][3] The protein is synthesized as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine.[4] A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers.[5] Both the mature protein and a partially processed form of the hormone can be secreted after cleavage of the propeptide.[5]
  • Lymphotoxin-alpha, formerly known as Tumor necrosis factor-beta (TNF-β), is a cytokine that is inhibited by interleukin 10.[6]

Family members[edit]

Nineteen cytokines have been identified as part of the TNF family on the basis of sequence, functional, and structural similarities.[7] They include:[8][9][10]

  • Tumor Necrosis Factor (TNF) (also known as cachectin [11] or TNF alpha)[12][13] is a cytokine that 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; 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 that are cytotoxic for a wide range of tumor cells in vitro and in vivo.[14]
  • T cell antigen gp39 (CD40L), a cytokine that seems to be important in B-cell development and activation.
  • CD27L, a cytokine that plays a role in T-cell activation. It induces the proliferation of co-stimulated T cells and enhances the generation of cytolytic T cells.
  • CD30L, a cytokine that induces proliferation of T cells.
  • FASL, a cytokine involved in cell death.[15]
  • 4-1BBL, an inducible T cell surface molecule that contributes to T-cell stimulation.
  • OX40L, a cytokine that co-stimulates T cell proliferation and cytokine production.[16]
  • TNF-related apoptosis inducing ligand (TRAIL), a cytokine that induces apoptosis.[17]
Model of hydrogen bond between Asn34 of subunit A and Arg82 of subunit C, produced by M. musculus, based on PDB structure 2TNF. The residues participating the hydrogen bond are shown in stick. The short bond length, 2.84Å, highly suggests a strong hydrogen bond that supports the tertiary structure. Baeyens, KJ et al. (1999).[1] Generated in Chimera.

All these cytokines seem to form homotrimeric (or heterotrimeric in the case of LT-alpha/beta) complexes that are recognized by their specific receptors. Strong hydrogen bonds between the monomers stabilize the tertiary structure. One such example is the Asn34-Arg82 hydrogen bond in the M. musculus TNF alpha.[1] The PROSITE pattern for this family is located in a beta-strand in the central section of the protein that is conserved across all members.

All members of the TNF family, with the exception of the secreted lymphotoxin and a proliferation-inducing ligand (APRIL), are type II transmembrane proteins that protrude from immune cells. Such membrane-bound TNF ligands frequently signal back to the immune cells when they contact and bind their cognate receptors on other cells.[7]

Cytokines can be grouped into a family on the basis of sequence, functional and structural similarities.[8][9][10] 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.[2][3] The protein is synthesised as a prohormone with an unusually long and atypical signal sequence, which is absent from the mature secreted cytokine.[4] A short hydrophobic stretch of amino acids serves to anchor the prohormone in lipid bilayers.[5] Both the mature protein and a partially processed form of the hormone are secreted after cleavage of the propeptide.[5]

Examples[edit]

Human proteins containing this domain include:

Notes and references[edit]

This article incorporates text from the public domain Pfam and InterPro IPR006052

  1. ^ a b c Baeyens KJ, De Bondt HL, Raeymaekers A, Fiers W, De Ranter CJ (April 1999). "The structure of mouse tumour-necrosis factor at 1.4 Å resolution: towards modulation of its selectivity and trimerization". Acta Crystallogr. D Biol. Crystallogr. 55 (Pt 4): 772–8. PMID 10089307. 
  2. ^ a b Fransen L, Müller R, Marmenout A, Tavernier J, Van der Heyden J, Kawashima E, Chollet A, Tizard R, Van Heuverswyn H, Van Vliet A (June 1985). "Molecular cloning of mouse tumour necrosis factor cDNA and its eukaryotic expression". Nucleic Acids Res. 13 (12): 4417–29. doi:10.1093/nar/13.12.4417. PMC 321797. PMID 2989794. 
  3. ^ a b Kriegler M, Perez C, DeFay K, Albert I, Lu SD (April 1988). "A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: ramifications for the complex physiology of TNF". Cell 53 (1): 45–53. doi:10.1016/0092-8674(88)90486-2. PMID 3349526. 
  4. ^ a b Sherry B, Jue DM, Zentella A, Cerami A (December 1990). "Characterization of high molecular weight glycosylated forms of murine tumor necrosis factor". Biochem. Biophys. Res. Commun. 173 (3): 1072–8. doi:10.1016/S0006-291X(05)80895-2. PMID 2268312. 
  5. ^ a b c d Cseh K, Beutler B (September 1989). "Alternative cleavage of the cachectin/tumor necrosis factor propeptide results in a larger, inactive form of secreted protein". J. Biol. Chem. 264 (27): 16256–60. PMID 2777790. 
  6. ^ Waltenbaugh C, Doan T, Melvold R, Viselli S (2008). Immunology. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins. p. 68. ISBN 0-7817-9543-5. 
  7. ^ a b Sun M, Fink PJ (2007). "A new class of reverse signaling costimulators belongs to the TNF family". J Immunol. 179 (7): 4307–12. PMID 17878324. 
  8. ^ a b Peitsch MC, Jongeneel CV (February 1993). "A 3-D model for the CD40 ligand predicts that it is a compact trimer similar to the tumor necrosis factors". Int. Immunol. 5 (2): 233–8. doi:10.1093/intimm/5.2.233. PMID 8095800. 
  9. ^ a b Farrah T, Smith CA (July 1992). "Emerging cytokine family". Nature 358 (6381): 26. doi:10.1038/358026b0. PMID 1377364. 
  10. ^ a b Bazan JF (September 1993). "Emerging families of cytokines and receptors". Curr. Biol. 3 (9): 603–6. doi:10.1016/0960-9822(93)90009-D. PMID 15335677. 
  11. ^ D. CAPUT, et al., Identification of a common nucleotide sequence in the 3'-untranslated region of mRNA molecules specifying inflammatory mediators, Proc. Natl. Acad. Sci. USA 83:1670-1674 Biochemistry, 1986 and references cited)
  12. ^ Beutler B, Cerami A (October 1988). "The history, properties, and biological effects of cachectin". Biochemistry 27 (20): 7575–82. doi:10.1021/bi00420a001. PMID 3061461. 
  13. ^ Vilcek J, Lee TH (April 1991). "Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions". J. Biol. Chem. 266 (12): 7313–6. PMID 1850405. 
  14. ^ Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP, Hession C, O'Brine-Greco B, Foley SF, Ware CF (March 1993). "Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface". Cell 72 (6): 847–56. doi:10.1016/0092-8674(93)90574-A. PMID 7916655. 
  15. ^ Suda T, Takahashi T, Golstein P, Nagata S (December 1993). "Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family". Cell 75 (6): 1169–78. doi:10.1016/0092-8674(93)90326-L. PMID 7505205. 
  16. ^ Baum PR, Gayle RB, Ramsdell F, Srinivasan S, Sorensen RA, Watson ML, Seldin MF, Baker E, Sutherland GR, Clifford KN (September 1994). "Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-1-regulated protein gp34". EMBO J. 13 (17): 3992–4001. PMC 395319. PMID 8076595. 
  17. ^ Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA (December 1995). "Identification and characterization of a new member of the TNF family that induces apoptosis". Immunity 3 (6): 673–82. doi:10.1016/1074-7613(95)90057-8. PMID 8777713. 

External links[edit]

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TNF(Tumour Necrosis Factor) family Provide feedback

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Literature references

  1. Copley RR; , J Mol Med 1999;77:361-363.: The gene for X-linked anhidrotic ectodermal dysplasia encodes a TNF- like domain. PUBMED:10353440 EPMC:10353440


Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry 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.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan C1q_TNF (CL0100), which has the following description:

The members of the C1q and TNF superfamily are involved in a diverse set of functions, which include: defense, inflammation, apoptosis, autoimmunity differentiation, organogenesis, hibernation and insulin-resistant obesity [1]. Both C1q and TNF domains form a compact jelly-roll beta- sandwich. The core of these structures are conserved between the two families and corresponds to the detectable sequence similarity. Proteins containing both of these domains, form trimers before they are active. However, the surfaces of the domains are quite different and this difference is thought to give rise to the function difference between the clan members[1].

The clan contains the following 2 members:

C1q TNF

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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  Seed
(52)
Full
(1178)
Representative proteomes NCBI
(1150)
Meta
(10)
RP15
(63)
RP35
(98)
RP55
(204)
RP75
(481)
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  Seed
(52)
Full
(1178)
Representative proteomes NCBI
(1150)
Meta
(10)
RP15
(63)
RP35
(98)
RP55
(204)
RP75
(481)
Alignment:
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  Seed
(52)
Full
(1178)
Representative proteomes NCBI
(1150)
Meta
(10)
RP15
(63)
RP35
(98)
RP55
(204)
RP75
(481)
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Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Prosite
Previous IDs: none
Type: Domain
Author: Finn RD
Number in seed: 52
Number in full: 1178
Average length of the domain: 120.10 aa
Average identity of full alignment: 23 %
Average coverage of the sequence by the domain: 49.88 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.9 20.9
Trusted cut-off 20.9 21.1
Noise cut-off 20.8 20.8
Model length: 127
Family (HMM) version: 13
Download: download the raw HMM for this family

Species distribution

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Interactions

There are 5 interactions for this family. More...

BaffR-Tall_bind TACI-CRD2 TNFR_c6 BCMA-Tall_bind TNF

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the TNF domain has been found. There are 271 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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