| Literature References | 1. FRANSEN, L., MULLER, R., MARMENOUT, A., TAVERNIER, J., VAN DER
HEYDEN, J., KAWASHIMA, E., CHOLLET, A., TIZARD, R., VAN HEUVERSWYN, H.
AND VAN VLIET, A.
Molecular cloning of mouse tumour necrosis factor cDNA and its eukaryotic
expression.
NUCLEIC ACIDS RES. 13 4417-4429 (1985).
2. KRIEGLER, M., PEREZ, C., DEFAY, K., ALBERT, I. AND LU, S.D.
A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane
protein: ramifications for the complex physiology of TNF.
CELL 53 45-53 (1988).
3. SHERRY, B., JUE, D.M., ZENTELLA, A. AND CERAMI, A.
Characterization of high molecular weight glycosylated forms of murine
tumor necrosis factor.
BIOCHEM.BIOPHYS.RES.COMMUN. 173 1072-1078 (1990).
4. CSEH, K. AND BEUTLER, B.
Alternative cleavage of the cachectin/tumor necrosis factor propeptide
results in a larger, inactive form of secreted protein.
J.BIOL.CHEM. 264 16256-16260 (1989).
5. JONES, E.Y., STUART, D.I. AND WALKER, N.P.
Structure of tumour necrosis factor.
NATURE 338 225-228 (1989).
6. VAN OSTADE X., TAVERNIER J., PRANGE T. AND FIERS W.
Localization of the active site of human tumour necrosis factor (hTNF) by
mutational analysis.
EMBO J. 10 827-836 (1991).
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| Documentation | Tumor necrosis factor (TNF) (or cachectin) is a monocyte-derived cytotoxin
that has been implicated in tumour regression, septic shock and cachexia
[1,2]. The protein is synthesised as a prohormone with an unusually long
and atypical signal sequence, which is absent from the mature secreted
cytokine [3]. A short hydrophobic stretch of amino acids serves to anchor
the prohormone in lipid bilayers [4]. Both the mature protein and a
partially-processed form of the hormone are secreted after cleavage of the
propeptide [4].
The structure of TNF has been determined to 2.9A using X-ray crystallography
[5]. The protein is trimeric, each subunit consisting of an anti-parallel
beta-sandwich. The subunits trimerise via a novel edge-to-face packing of
beta-sheets [5]. Comparison of the subunit fold with that of other proteins
reveals similarity to the `jelly-roll' structural motif characteristic of
viral coat proteins [5]. It is believed that each TNF molecule has three
receptor-interaction sites (between the three subunits), thus allowing
signal transmission by receptor clustering [6].
TNECROSISFCT is a 5-element fingerprint that provides a signature for
tumour necrosis factors. The fingerprint was derived from an initial
alignment of 21 sequences: the motifs were drawn from conserved regions
spanning virtually the full alignment length - motif 1 includes beta-strand
1; motif 2 spans strands 2 and 3; motif 3 encodes strands 6 and 7; motif 4
spans strands 9 and 10; and motif 5 encodes strand 11. Two iterations on
SPTR37_10f were required to reach convergence, at which point a true set
comprising 30 sequences was identified.
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