The death domain [1,2,3] (FAS/TNF cytosolic interaction domain) has first been described as a region in the cytoplasmic tail of the 75 Kd TNF receptor (TNFR-1) (see <PDOC00561>) which is involved in TNF-mediated cell death signaling. A corresponding region is found in the cytoplasmic tail of FAS/APO1 another surface receptor inducing apoptotic cell death. This region mediates self-association of these receptors, thus giving the signal to downstream events leading to apoptosis.

Subsequently, a number of other proteins have been found to interact with the cytoplasmic part of either FAS or the TNF receptor in the region of the death domain. Overexpression of these proteins usually leads to cell death. By profile analysis, it has been shown that a number of other proteins contain regions with significant similarity to the death domain. Interestingly, several of these proteins also work in the context of cell death signaling.

The following proteins have been found to contain a death domain:

• Tumor Necrosis Factor type I (TNFR-1), which induces cell death upon binding of TNF.
• FAS/APO1 receptor, which induces cell death upon binding of FAS-ligand.
• Low-affinity nerve growth factor receptor (LA-NGFR), which is involved in inducing cell death, sensing the absence of it's ligand NGF.
• Wsl-1, a receptor that mediates apoptosis.
• MORT1/FADD, a human protein that binds to the death domain of FAS/APO1 and induces apoptosis.
• TRADD, a human protein that binds to TNFR-1, signaling cell death and NF-kB activation.
• RIP, a human protein that interacts with FAS/APO1 and weakly with TNFR-1 and induces cell death. Rip contains a protein kinase domain at its N- terminus.
• All known isoforms of ankyrin, this includes the ankyrin-like protein unc- 44 from Caenorhabditis elegans. Ankyrin is a protein that attaches the cytoskeleton to the plasma membrane.
• Human 'death associated protein kinase' (DAP-kinase), a mediator of γ- interferon induced cell death.
• p84, a human protein that binds to the N-terminus of the Rb-protein.
• MyD88, a mouse macrophage differentiation marker that also contains a TOLL/IL1R-domain.
• Unc-5, a Caenorhabditis elegans receptor-type neuronal guidance protein.
• Pelle, a protein kinase from Drosophila involved in the Toll/Dorsal signaling pathway.
• Reaper, a cell death mediating protein from Drosophila, has also been reported [4] to contain a death domain. However, rigorous sequence analysis [2] does not statistically confirm the presence of such a domain.

In most of these proteins, the death domain is located at the extreme C-terminus. Exceptions are ankyrin, MyD88 and pelle, all protein probably not directly involved in cell death signaling. In the case of ankyrin, the isoform 2.1 is a splice variant which has the death domain located at the C-terminus.

The profile covers the complete domain up to the boundaries that define a minimally functional death domain in FAS and TNF-receptor. This region is slightly bigger than the observed sequence conservation.