Taxonomic distribution of proteins containing DEATH domains

The DEATH domain within your query sequence starts at position 262 and ends at position 356, and its E-value is 7e-18.

NMR structure of the death domain of the p75 neurotrophin receptor.

Liepinsh E, Ilag LL, Otting G, Ibanez CF
EMBO J. 1997; 16: 4999-5005

The intracellular domain of the p75 neurotrophin receptor (p75ICD) lacks catalytic activity but contains a motif similar to death domains found in the cytoplasmic regions of members of the tumor necrosis factor receptor family and their downstream targets. Although some aspects of the signaling pathways downstream of p75 have been elucidated recently, mechanisms of receptor activation and proximal signaling events are unknown. Here we report the nuclear magnetic resonance (NMR) structure of the 145 residue long p75ICD. The death domain of p75ICD consists of two perpendicular sets of three helices packed into a globular structure. The polypeptide segment connecting the transmembrane and death domains as well as the serine/threonine-rich C-terminal end are highly flexible in p75ICD. Unlike the death domains involved in signaling by the TNF receptor and Fas, p75ICD does not self-associate in solution. A surface area devoid of charged residues in the p75ICD death domain may indicate a potential site of interaction with downstream targets.

An antagonist decoy receptor and a death domain-containing receptor for TRAIL.

Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM
Science. 1997; 277: 815-8

TRAIL, also called Apo2L, is a cytotoxic protein that induces apoptosis of many transformed cell lines but not of normal tissues, even though its death domain-containing receptor, DR4, is expressed on both cell types. An antagonist decoy receptor (designated as TRID for TRAIL receptor without an intracellular domain) that may explain the resistant phenotype of normal tissues was identified. TRID is a distinct gene product with an extracellular TRAIL-binding domain and a transmembrane domain but no intracellular signaling domain. TRID transcripts were detected in many normal human tissues but not in most cancer cell lines examined. Ectopic expression of TRID protected mammalian cells from TRAIL-induced apoptosis, which is consistent with a protective role. Another death domain-containing receptor for TRAIL (designated as death receptor-5), which preferentially engaged a FLICE (caspase-8)-related death protease, was also identified.

Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death.

Boldin MP, Goncharov TM, Goltsev YV, Wallach D
Cell. 1996; 85: 803-15

Fas/APO-1 and p55 tumor necrosis factor (TNF) receptor (p55-R) activate cellular mechanisms that result in cell death. Upon activation of these receptors, Fas/APO-1 binds a protein called MORT1 (or FADD) and p55-R binds a protein called TRADD. MORT1 and TRADD can also bind to each other. We have cloned a novel protein, MACH, that binds to MORT1. This protein exists in multiple isoforms, some of which contain a region that has proteolytic activity and shows marked sequence homology to proteases of the ICE/CED-3 family. Cellular expression of the proteolytic MACH isoforms results in cell death. Expression of MACH isoforms that contain an incomplete ICE/CED-3 region provides effective protection against the cytotoxicity induced by Fas/APO-1 or p55-R triggering. These findings suggest that MACH is the most upstream enzymatic component in the Fas/APO-1- and p55-R-induced cell death signaling cascades.

NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain.

Huang B, Eberstadt M, Olejniczak ET, Meadows RP, Fesik SW
Nature. 1996; 384: 638-41

Programmed cell death (apoptosis) mediated by the cytokine receptor Fas is critical for the removal of autoreactive T cells, the mechanism of immune privilege, and for maintenance of immune-system homeostasis. Signalling of programmed cell death involves the self-association of a conserved cytoplasmic region of Fas called the death domain and interaction with another death-domain-containing protein, FADD (also known as MORT1). Although death domains are found in several proteins, their three-dimensional structure and the manner in which they interact is unknown. Here we describe the solution structure of the Fas death domain, as determined by NMR spectroscopy. The structure consists of six antiparallel, amphipathic alpha-helices arranged in a novel fold. From the structure and from site-directed mutagenesis, we have identified the region of the death domain involved in self-association and binding to the downstream signalling partner FADD.

The death domain motif found in Fas (Apo-1) and TNF receptor is present in proteins involved in apoptosis and axonal guidance.

Hofmann K, Tschopp J
FEBS Lett. 1995; 371: 321-3

The interaction of Fas (Apo-1) and TNF receptor-1 with their respective ligands can lead to cell death. The so-called death domain, a sequence motif present in the cytoplasmic portion of the two receptors, has been identified as a critical structural element involved in signal transduction that leads to apoptosis. Here we describe several additional proteins which contain a death domain. Novel members of this family include proteins known to be implicated not only in apoptosis but also in neuron guidance.

A novel protein domain required for apoptosis. Mutational analysis of human Fas antigen.

Itoh N, Nagata S
J Biol Chem. 1993; 268: 10932-7

The Fas antigen is a cell surface protein that can mediate apoptosis and that belongs to the tumor necrosis factor receptor family. Murine fibroblast L929 cells or T-cell lymphoma WR19L cells expressing the human Fas antigen were killed within 4-6 h by anti-human Fas antibody in a concentration-dependent manner. Human Fas antigen cDNAs with various mutations in the cytoplasmic region were constructed and expressed in L929 cells. A deletion of 15 amino acids from the C terminus of the Fas antigen enhanced the Fas antibody-induced killing activity, whereas a further deletion abolished its activity. This suggests the presence of an inhibitory as well as a signal-transducing domain in the cytoplasmic region of the Fas antigen. A 68-amino acid portion of the signal-transducing domain significantly conserved in the Fas antigen as well as in the type I tumor necrosis factor receptor was considered to be the novel protein domain required for apoptotic signal transduction.