ApoReview-Introduction to Apoptosis:Page 9 of 26 Intrinsic apoptosis pathways (Fig.5)involve procaspase-9 which is activated downstream of mitochondrial proapoptotic events at the so called apoptosome,a ytosolic death signalling protein complex that is formed upon release of cytochrome c from the mitochondria [Salvesen,2002b].In this case it is the dimerization of procaspase-9 molecules at the Apaf-I scaffold that is responsible for caspase-activation [Denault,2002]Once the initiator caspases have been activated,they can proteolytically activate the effector procaspases-3.6,and-7 which subsequently cleave a specific set of protein substrates,including procaspases themselves,resulting in the mediation and amplification of the death signal and eventually in the execution of cell death with all the morphological and biochemical features usually observed [Earnshaw,1999]. A.Mitochondrial pathway of caspase activation →→ B.Apoptosome formation and activation Apoptosome that allows the fo of a hep enc. vhee like structure.the apoptosome. Procaspase-g 5oset5e的1op9ypouogeeeep9uBu3969eUse西GWNpydApoReview - Introduction to Apoptosis: Page 9 of 26 Intrinsic apoptosis pathways (Fig. 5) involve procaspase-9 which is activated downstream of mitochondrial proapoptotic events at the so called apoptosome, a cytosolic death signalling protein complex that is formed upon release of cytochrome c from the mitochondria [Salvesen, 2002b]. In this case it is the dimerization of procaspase-9 molecules at the Apaf-1 scaffold that is responsible for caspase-9 activation [Denault, 2002]. Once the initiator caspases have been activated, they can proteolytically activate the effector procaspases-3, -6, and -7 which subsequently cleave a specific set of protein substrates, including procaspases themselves, resulting in the mediation and amplification of the death signal and eventually in the execution of cell death with all the morphological and biochemical features usually observed [Earnshaw, 1999]. WD40 CARD WD40 Apaf-1 Cyto C dATP WD40 WD40 CARD Cyto C 7 x Active Caspase-9 dimers WD40 WD40 Cy ot C WD40 WD40 Cy ot C CARD CARD „hub“ plane CARD CARD CARD CARD CARD CARD Pro￾Caspase-9 Mitochondria Apoptotic Stimulus Cyto c release Formation of the Apoptosome Activation of Caspase-9 A. Mitochondrial pathway of caspase activation B. Apoptosome formation and activation Apoptosome WD40 CARD WD40 Apaf-1 Cyto C dATP WD40 WD40 CARD Cyto C 7 x Active Caspase-9 dimers WD40 WD40 Cy ot C WD40 WD40 Cy ot C CARD CARD „hub“ plane CARD CARD CARD CARD CARD CARD Pro￾Caspase-9 Mitochondria Apoptotic Stimulus Cyto c release Formation of the Apoptosome Activation of Caspase-9 A. Mitochondrial pathway of caspase activation B. Apoptosome formation and activation Apoptosome Fig. 5 Mitochondria-mediated caspase activation at the apoptosome. A. Apoptotic stimuli trigger the release of apoptogenic factors from the mitochondrial intermembrane space to the cytosol, such as cytochrome c which induces the formation of the apoptosome and the activation of procaspase- 9. B. By the action of cytochrome c (Cyto C) and dATP the Apaf-1 protein adopts a conformation that allows the formation of a heptameric, wheel-like structure, the apoptosome. Procaspase-9 molecules can bind to the inner “hub” region of the apoptosome and are activated by dimer formation. Active caspase-9 dimers further mediate activation of effector caspases [Acehan, 2002]