Homology between reaper and the cell death domains of Fas and TNFR1
نویسندگان
چکیده
When engaged by antibodies or by their respective li-gands, the cell surface molecules Fas and TNFR1 (the 55 kDa tumor necrosis factor [TNF] receptor) can transduce into cells a signal that often leads to cell death (Armitage, 1994; Nagata and Golstein, 1995). Fas and TNFR1 have homologous extracellular cysteine-rich domains that make them members of the nerve growth factor receptor super-family. They are also homologous in their cytoplasmic regions for a stretch of 60-70 amino acids, called the death domain, which makes them different from most other members of this superfamily. This dual but dissociated homology, the autonomous death signaling ability of the fact that they are encoded within the last exon of their respective genes (Behrmann et al., 1994) suggest that Fas and TNFR1 may derive from a chimeric ancestor molecule. Such a molecule would have brought together an extracellular region, ancestor to a nerve growth factor receptor domain, and an intracellular cell death signaling module. We reasoned that a derivative of the latter might still exist as an autonomous entity and therefore looked for an intracellular molecule involved in cell death and of about the same size as the death domains. Reaper, discovered through an elegant genetic approach by White et al. (1994), is a 65 amino acid peptide, the expression of which is both necessary and sufficient for developmental cell death and at least some types of experimental cell death in Drosophila. Mere visual inspection showed homology between reaper and the death domains of TNFR1 and, to a lesser extent, of Fas (Figure 1). This homology was particularly significant because it involves Drosophila and mammalian molecules and because all of these are able to signal cell death. Closer inspection suggested some heterogeneity in the distribution of homologies along reaper. In particular, the middle third of reaper shows the highest density of homologies with TNFRI. Reaper is involved in a pathway signaling cell death in Drosophila (White et al., 1994). Expression of reaper is both necessary and sufficient to proceed to the next step of this pathway (White et al., 1994). The emergence during evolution of a chimeric molecule covalently linking reaper to an extracellular module would have allowed direct access from the cell exterior to this cell death signaling pathway. For instance, a cell death pathway would thereby have become directly accessible via Fas to cytotoxic T cells bearing the Fas ligand (Rouvier et al., 1993; Suda …
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ورودعنوان ژورنال:
- Cell
دوره 81 شماره
صفحات -
تاریخ انتشار 1995