Death domain

So far ten catalytically active caspases have been reported in mouse (caspase-1, -2, -3, -6, -7, -8, -9, -11, -12,-14) and eleven in human (caspase-1, -2, -3, -4, -5, -6, -7, -8, -9, -10, -14) (Fig. 1). Caspases are expressed as inactive proenzymes that contain an amino-terminal prodomain of variable length followed by two domains with conserved sequences a large subunit ( 20 kDa, p20) and a small carboxy-terminal subunit ( 10 kDa, plO). Caspases can be divided according to absence (-3, -6, -7, -14) or presence (-1, -2, -8, -9, -10, -11, -12) of an extended prodomain containing protein-protein interaction motifs belonging to the death domain (DD) superfamily, in particular the death effector domains (DED) and the caspase activation and recruitment domains (CARD). 

ALT, alanine aminotransferase ASC, apoptosis-associated speck-like protei containing a CARD AST, aspartate aminotransferase CARD, caspase activation and recruitment domains CD, Crohn s disease COP, CARD-only protein DD, death domain DED, death effector domains DIABLO, direct LAP-binding protein with low pi... 

Death domain (DD) superfamily consists of structurally related homotypic interaction motifs of approximately 90 amino acids. The motifs are organized in six antiparallel amphipathic a-helices, the so-called DD fold. The four members of the super family are the death domain (DD), the death effector domain (DED), the caspase activation and recruitment domain (CARD), and the Pyrin domain. All are important mediators for the assembly of caspase activating complexes. 

MyD88 was the first adapter protein to be discovered. As well as the TER. domain it contains a death domain (DD). MyD88 is used by all TLRs to signal with the exception of TLR-3, which requires TRIF. Its signalling pathway is outlined in Fig. 2. 

Death Domain and Death Receptors Death Domain Superfamily Defensins... 

DEATH DEATH domain, found in proteins involved in cell death (apoptosis) E(M)B 0(0) 9(9) 1DDF... 

Boldin, M.P., Mett, I.L., Varfolomeev, E.E., Chumakov, 1., Shemer-Avni, Y., Camonis, J.H. and WaUach, D., 1995, Self-association of the death domain of the p55 tumor necrosis factor (TNF) receptor and Fas/APOl prompts signaling for TNF and Fas/APOl effects. J. Biol. Chem. 270 387-391... 

JeHe, A., Bock, J., MueUer, C., Kun, J. and Gulbins E. 2001, The CD95 death domain is required for acid sphingomyehnase mediated receptor clustering. In prep. 

Berglund, H., Olerenshaw, D., Sankar, A., Federwisch, M., McDonald, N. Q., and DriscoU, P. C., 2000, The three-dimensional solution stmcture and dynamic properties of the human FADD death domain. J Mol Biol 302 171-188. 

Chinnaiyan, A. M., O Rourke, K., Tewari, M., and Dixit, V. M., 1995, FADD, a novel death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell SI 505-512. 

Figure 2. Mechanisms and signalings of neuronal death. Death can be initiated at the membrane by activation of death domain receptors (DDR), or by intracellular signalings through oxidative stress (and the production of reactive oxigen species, ROS), perturbed calcium homeostasis, mitochondrial dysfunction (release of cytochrome c, cytC), activation of caspases, as well as reactivation of cell cycle genes such as the transcription factor E2F (see text). Interconnections have been demonstrated (dotted lines) depending on the apoptotic context...

An important trigger for apoptosis is known as the Fas system. This is used by cytotoxic Tcells, for example, which eliminate infected cells in this way (top left). Most of the body s cells have Fas receptors (CD 95) on their plasma membrane. If a T cell is activated by contact with an MHC presenting a viral peptide (see p. 296), binding of its Fas ligands occurs on the target cell s Fas receptors. Via the mediator protein FADD ( Fas-associated death domain ), this activates cas-pase-8 inside the cell, setting in motion the apoptotic process. 

VIO. Vincenz, C., and Dixit, V. M., Fas-associated death domain protein interleukin-1 betaconverting enzyme 2 (ET.1CE2), an ICE/Ced-3 homologue, is proximally involved in CD95- and p55-mediated death signaling. J. Biol. Chem. Ill, 6578-6583 (1997). 

Fig. 5. A hypothetical model of the structure/function relationship between wild-type mFas and sFas variants. A requirement for the normal signahng process is to form homotrimers of the complete mFas molecules. sFas can also trimerize with wild-type mFas, suggesting that such an aberrant trimerization results in disruption of the signahng. Fas-L, Fas ligand DD, death domain aa, amino acid.

The majority of these somatic mutations are heterozygous and located in the intracytoplasmic (IC) domain, which contains the death domain, as summarized in Table 2. The literature shows that 89.5% of the mutations are detected in exons 5.3% in exon 2, 3.9% in exon 3, 3.9% in exon 4, 7.9% in exon 6, 2.6% in exon 7, 1.3% in exon 8, and 64.5% in exon 9. In contrast, only 10.5% of the mutations are reported to occur in introns. All mutations in introns reportedly occur at 5 or 3 splice sites and cause probably aberrant splicing, resulting in premature termination... 

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