Caspases death effector 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. 

Activation of the caspases requires the help of a number of cofactors that are also known as activators or adaptors. Different cofactors are involved depending on the trigger mechanism of caspase activation. A central function of the cofactors is to bring about aggregation and thus activation of the procaspases. This occurs by specific protein-protein interactions with the help of common structural motives. Examples of such motives are the death domains (DD), death effector domains (DED) and the caspase recruitment domains (CARD), which all have a similar structure of six a-heh-ces. 

In the case of the death receptor Fas (see 15.4), activation of the caspase involves a protein that interacts with the cytoplasmic part of the receptor and is known as FADD protein (Fas-associated death domain). The FADD protein has distinct structural motives that mediate specific interactions with other proteins. It interacts via the death domain with the receptor and via the death effector domain with the corresponding caspase (here caspase 8). 

Binding of the ligand of the Fas receptor triggers clustering of the receptor and association of the cofactor FADD (fas-assodated protein with death domain) which interacts with the receptor via its death domain (DD). Procaspase 8 binds to FADD via a common DED (death effector domain) motif and is thereby also recruited into the Fas-receptor associated complex. Due to the clustering of the proteins, proximity-induced cleavage of procaspase 8 to the mature initiator caspase 8 takes place. This activates the effector caspases and triggers cell death. 

Caspase family. This scheme illustrates the domain structures, internal cleavage sites, preferred peptide substrate sequences, and biological function of caspases. Each procaspase consists of a large and small domain and may also possess DED (death effector domain) and CARD (caspase recruitment domain) (adapted from Hill etai, 2003). 

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],... 

Apoptosis PCR microarray is a relatively new methodology that uses real-time PCR to profile the expression of at least 112 key genes involved in apoptosis. The array includes the TNF ligands and their receptors members of the bcl-2, caspase, IAP, TRAF (TNF receptor associated factor), CARD (caspase activation and recruitment domain), death domain, death effector domain, and CIDE (cell death-inducing DFFA-like effector) families and genes involved in the p53 and ATM pathways. Also included in the evaluation are genes involved in anti-apoptosis. This assay allows for the evaluation of the expression of a focused panel of genes related to apoptosis. 

Receptors that contain an intracellular DD are known as death receptors, which are exemplified by Fas and TNF-Rl (Ashkenazi and Dixit, 1998 Nagata, 1997). Fas is an effective prototypical cell killing receptor. The intracellular DD of Fas directly recruits a DD-containing protein known as Fas-associated DD (FADD) via DD-DD interactions (Chinnaiyan et al, 1995). FADD also contains a death effector domain (DED), which further recruits the DED-containing pro-caspase-8 or pro-caspase-10 to elicit cas-pase activation and apoptosis (Boldin et al, 1996 Muzio et al, 1996 Wang et al, 2001b). 

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. 

Initiator caspases involved in the apoptotic process. These caspases, also known as apical caspases, are structurally characterized by the presence of a long prodomain at the N-terminal region containing different protein-protein interaction motifs such as death effector domain (DED) found in caspase-8 and-10 or caspase recruitment domain (CARD), present in caspase-2 and -9. Via... 

Recruitment of the initiator procaspases into a multiprotein complex results from a regulated series of protein-protein interactions mediated by interaction modules . Four types of interaction modules are involved in the activation of initiator caspases and thus play important roles in the initiation of apoptosis (review Weber and Vin-cenz, 2001). These domains have been named the death domain (DD),, the death effector domain (DED), the caspase activation and recruitment domain (CARD), and the less characterized pyrin domain. The domains are found on several components of the apoptotic signaling pathways and mediate homotypic protein-protein interactions, i. e., a given module will interact only with a member of the same family and not with members of the other families. Since members of the same module are found on different proteins, these modules mediate the assembly of hetero-oligomeric protein complexes. As examples, DDs are found on death receptors and their cofactors, D EDs on cofactors and the initiator caspase-8, and CARDS on cofactors, caspase-2, and caspase-9. 

Caspase-8 is recruited to FADD via interaction between death effector domains. We found that ORF E8 of the equine herpes virus-2 encoded a protein with two predicted death effector domains. This protein, called v-FLIP, is also present in several other viruses including human herpes virus-8. It interferes with the apoptotic pathway of FasL by binding to FADD and potently inhibits TRAIL-mediated cell death (Thome et al., 1997). The sequence information from v-FLIP led to the discovery of a mammalian homo-logue, cellular FLIP (c-FLIP, also called CASPER/I-... 

FasL binding induces the oligomerization of Fas via their death domains (DD) and the recruitment to the clustered receptors of the DD-containing adaptor molecule FADD. FADD contains an additional caspase recruitment domain, called death effector domain (DED), that binds to the DED of procaspase-8. Its activation initiates a cascade of proteolytic cleavages, involving downstream... 

Like other receptors, death receptors are activated by binding ligands. The activated death receptor-ligand complex is linked with its death domain (DD) to a homologous DED (death effector region), repeated in tandem, and recruits a zymogen form of a protease, pro-caspase 8 (Fig. 13.1). But the linker is, like other linkers, versatile. 

The TRADD or FADD domains bind to adapter proteins in the cytosol and together they form of a death inducing signaling complex (DISC). This complex recruits caspase-8, one of a family of calcium ion-activated serine proteases (caspases) which cleave polypeptides on the C-terminal side of their aspartate residues. DISC activates caspase-8 to activate a Bcl-2 activator, BID (Fig. 13.1 Oa). The resultant tBid fragment activates effector Bcl-2 proteins on the endoplasmic reticular membrane and mitochondrial outer membrane. 

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