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Figure 1 (A) One part of the MHC locus on chromosome 6, including the TNF gene complex. All TNF polymorphisms are included in the gene map: the (CT)n sequence microsatellites TNFb (7 alleles), TNFc (2 alleles), TNFd (7 alleles) and TNFe (3 alleles), the (CA)n sequence microsatellite TNFa (12 alleles), the microsatellite Tau-a (11 or 14 GTs), the restriction sites for EcoRI, AspHI and Ncol (TNFB*1/2), the single G/A exchanges at positions -163, -238, -308 (TNF1/2) and -376, and the C stretch (7 or 8 Cs) at +70

(membrane-bound TNFa, a type II transmembrane protein) and shows no glycosylation. The leader sequence entails a linking domain (amino acids -1 to —20, unnecessary for TNFa function), a hydrophobic transmembrane domain (-21 to —46) and a cytoplasmic domain (-47 to -76). There is an alternative cleavage site at position 11.

Murine TNFa has only 156 amino acids derived from a 235 amino acid precursor and is glycosylated. Despite these differences, protein sequences from porcine, bovine, goat, feline, rabbit, rat, murine and human TNFa show homologies between 70 and 90%. TNFa shows no species specificity but some species preferences in cross-reactivity.

Natural TNFa is a trimeric molecule with an antiparallel 3-sheet sandwich and an edge-ro-edge packing structural motif. Transmembrane TNFa is cleaved by metalloproteases, neutral serine protease 3 (PR-3) and matrix metalloproteases. Metallopro-teinase inhibitors arc effective in the treatment of rat endotoxemia and autoimmune inflammatory diseases by blocking both processing of membrane-bound TNF-a and shedding of the 75 kDa TNF receptor. Membrane-bound TNFa seems to be the natural and effective ligand for the 75 kDa receptor.

TNFa develops an intermediate dimer after cleavage from the membrane before forming the natural trimer. The dimer accumulates first and trimerization is finished within 6 minutes. The existence of a TNFa dimer may also be the natural correlate to TNF receptor dimerization.

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