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Tumor necrosis factor superfamily

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"TNF" redirects here. For the database normalization term, see Third normal form.
TNF(Tumor Necrosis Factor) family
Trimeric structure of 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
SymbolTNF
PfamPF00229
InterProIPR006052
PROSITEPDOC00224
SCOP21tnf / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

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

  • Tumor necrosis factor (TNF), formerly known as TNF-α, 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

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 or TNF-alpha)[11][12] 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.[13]
  • 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 costimulated 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.[14]
  • 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.[15]
  • TNF-related apoptosis inducing ligand (TRAIL), a cytokine that induces apoptosis.[16]
thumb

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 stabilizes 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 which 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]

Examples

Human proteins containing this domain include:

References

  1. ^ a b c Baeyens KJ, De Bondt HL, Raeymaekers A, Fiers W, De Ranter CJ (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Fransen L, Müller R, Marmenout A, Tavernier J, Van der Heyden J, Kawashima E, Chollet A, Tizard R, Van Heuverswyn H, Van Vliet A (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Kriegler M, Perez C, DeFay K, Albert I, Lu SD (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Sherry B, Jue DM, Zentella A, Cerami A (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b Cseh K, Beutler B (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  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.{{cite book}}: CS1 maint: multiple names: authors list (link)
  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. ^ Peitsch MC, Jongeneel CV (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  9. ^ Farrah T, Smith CA (1992). "Emerging cytokine family". Nature. 358 (6381): 26. doi:10.1038/358026b0. PMID 1377364. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Bazan JF (1993). "Emerging families of cytokines and receptors". Curr. Biol. 3 (9): 603–6. doi:10.1016/0960-9822(93)90009-D. PMID 15335677. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ Beutler B, Cerami A (1988). "The history, properties, and biological effects of cachectin". Biochemistry. 27 (20): 7575–82. doi:10.1021/bi00420a001. PMID 3061461. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ Vilcek J, Lee TH (1991). "Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions". J. Biol. Chem. 266 (12): 7313–6. PMID 1850405. {{cite journal}}: Unknown parameter |month= ignored (help)
  13. ^ Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP, Hession C, O'Brine-Greco B, Foley SF, Ware CF (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Suda T, Takahashi T, Golstein P, Nagata S (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Baum PR, Gayle RB, Ramsdell F, Srinivasan S, Sorensen RA, Watson ML, Seldin MF, Baker E, Sutherland GR, Clifford KN (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, Sutherland GR, Smith TD, Rauch C, Smith CA (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
This article incorporates text from the public domain Pfam and InterPro: IPR006052
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