ApoReview-Introduction to Apoptosis:Page 8 of26 Via their prodomains,the initiator caspases are recruited to and activated at death inducing signalling complexes either in response to the ligation of cell surface death receptors (extrinsic apoptosis pathways)or in response to signals originating from inside the cell(intrinsic apoptosis pathways). In extrinsic apoptosis pathways(Fig.4).e.g procaspase-is recruited by its DEDs to the death inducing signalling complex(DISC),a membrane receptor complex formed following to the ligation of a member of the tumor necrosis factor receptor (TNFR)family [Sartorius,2001].When bound to the DISC.several procaspase-8 molecules are in close proximity to each other and therefore are assumed to activate each other by autoproteolysis [Denault,2002]. Procaspaso-8 aa6.7一→APOPTOSIS active Caspase-8 Fig.4 Roceptomctetedoca5aseactaronmptcheDssgepn3sgeoae%ag9at69escbe possessing DDs,the adaptors additionally contain death effector domains (DED)which recruit which isa het bunits he initiatior caspase-8 cleaves and ereby a cror caspases for t si ApoReview - Introduction to Apoptosis: Page 8 of 26 Via their prodomains, the initiator caspases are recruited to and activated at death inducing signalling complexes either in response to the ligation of cell surface death receptors (extrinsic apoptosis pathways) or in response to signals originating from inside the cell (intrinsic apoptosis pathways). In extrinsic apoptosis pathways (Fig. 4), e.g. procaspase-8 is recruited by its DEDs to the death inducing signalling complex (DISC), a membrane receptor complex formed following to the ligation of a member of the tumor necrosis factor receptor (TNFR) family [Sartorius, 2001]. When bound to the DISC, several procaspase-8 molecules are in close proximity to each other and therefore are assumed to activate each other by autoproteolysis [Denault, 2002]. Ligand (FasL, TNF-α, TRAIL) Death Receptor (Fas, TNFR1, DR5, .) Adaptors (FADD, TRADD) D D D D D D D E D D D D E D D D D E D D E D Procaspase-8 D E D D E D active Caspase-8 Activation of Caspases-3, -6, -7 APOPTOSIS Ligand (FasL, TNF-α, TRAIL) Death Receptor (Fas, TNFR1, DR5, .) Adaptors (FADD, TRADD) D D D D D D D E D D D D E D D D D E D D E D Procaspase-8 D E D D E D active Caspase-8 Activation of Caspases-3, -6, -7 APOPTOSIS Fig. 4 Receptor-mediated caspase activation at the DISC. Upon ligation by its cognate ligand, the trimeric death receptor recruits adaptor molecules via its cytoplasmic death domains (DD). Besides possessing DDs, the adaptors additionally contain death effector domains (DED) which recruit procaspase-8 to the receptor complex which now is called the death-inducing signalling complex (DISC). Procaspase-8 is activated by autoproteolytic cleavage and forms the active caspase-8 which is a heterotetramer of two small and two large subunits. The initiatior caspase-8 cleaves and thereby activates effector caspases for the execution of apoptosis