Death Domain Superfamily

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

Weber CH, Vincenz C. The death domain superfamily A tale of two interfaces Trends Biochem Sri 2001 26 475 481. 

Structural studies have revealed that several other domains involved in cell death and inflammatory signaling transduction, including the death effector domain (DED) (Fig. 11C), the caspase recruitment domain (CARD) and the Pyrin domain (PYD), also possess the same six helix bundle structures of DDs (Chou et al, 1998 Eberstadt et al, 1998 Hiller et al, 2003), forming the death domain superfamily. Interestingly, interactions have only been observed among proteins within the same subfamilies with no cross interactions between proteins from different subfamilies. 

Weber, C. H., and Vincenz, C. (2001). A docking model of key components of the DISC complex Death domain superfamily interactions redefined. FEES Lett. 492, 171-176. 

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). 

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. 

There are two distinct types of TNF receptors, TNF-R1 (CD120a or P55) and TNF-R2 (CD120b or P75). They are implicated in inflammatory processes and both belong to the TNF receptor superfamily. TNF receptors are transmembrane proteins with intracellular domains that lack intrinsic enzymatic activity, and consequently, they require cytoplasmic proteins that help initiate the receptor-induced signaling pathways. TNF-R1 possesses an intracellular death domain and TNF-R2 interacts with molecules of the TNF receptor-associated factor 2 family (TRAF). 

The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to induce cell apoptosis. Through its death domain, this receptor interacts with TRADD protein, which is known to serve as an adaptor that mediates signal transduction of TNF receptors. Knockout studies in mice suggested that this gene plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation. 

The extrinsic pathway consists of a series of events initially induced by death receptors located on the cell surface. It is initiated by interaction of extracellular death ligands with their respective receptors, located on the surface of the plasma membrane. The death ligands are members of the tumor necrosis factor (TNF)/nerve growth factor (NGF) superfamily. TNF-R1, Fas (Apo-l/CD95), TRAIL-R1, TRAIL-R2, and NGF-R are examples of death receptors. They are transmembrane proteins consisting of an external domain, where the ligand associates, and a cytoplasmic domain, which contains the DD (death domain). 

The large prodomains of procaspases contain structural motifs that belong to the death domain (DD) superfamily involved in the transduction of the apoptotic signals. This superfamily consists of the DD, the death effector domain (DED), and the caspase recruitment domain (CARD). Each of these motifs interacts with other proteins by homotypic interactions. DED is found in procaspase-8 and -10, and CARD is found in procaspase-1, -2, -4, -5, -9, -11, and -12. DED and CARD are responsible for the recruitment of initiator caspases into death- or inflammation-inducing signaling complexes, resulting in proteolytic autoactivation of caspases that subsequently initiates inflammation and apoptosis [26, 29, 30],... 

The neurotrophin receptor p75 was first identified as a nerve growth factor (NGF)-binding protein and was subsequently shown to interact with each of the other neurotrophic factors, BDNF, neurotrophin-3, and neurotrophin-4/-5. It also modulates the activity of several members of the tropomyosin-related receptor tyrosine kinase family (Trk) (reviewed in Chao, 2003). p75, a member of the tumor necrosis factor superfamily, is a type I transmembrane protein with four cysteine-rich domains in its extracellular region and a Death domain in its cytoplasmic protein (Fig. 11). 

Upon receptor activation, different intracellular signaling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences (Fig. 1). Receptors that do not contain a structural module known as the death domain (DD) in their intracellular domains are survival receptors, which directly recruit adapter... 

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