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\MhereasBak is tightly bound to the mitochondrial outermembrane even in the absence of an apoptotic signal, Bax is mainly Iocated inthe cltosol and translocates to the mitochondria only after an apoptotic signalactivates it. As we discuss below the activation of Bax and Bak usually dependson activated pro-apoptotic BH3-only proteins. Both Bax and Bak also operate onthe surface of the endoplasmic reticulum (ER) and nuclear membranes; whenactivated in response to ER stress, they are thought to release Ca2* into thecytosol, which helps activate the mitochondrial-dependent intrinsic pathway ofapoptosis by a poorly understood mechanism.The anti-apoptotic Bcl2 proteins such as Bcl2 itself and Bcl-X1 are alsomainly located on the cltosolic surface of the outer mitochondrial membrane,the ER, and the nuclear envelope, where they help preserve the integrity of theFigure18-8 The intrinsicpathwayofapoptosis.(A)A schematicdrawingof howcytochromec releasedfrom mitochondriaactivatesApaf1.The bindingofcytochromec causesthe Apafl tohydrolyzeits bound dATPto dADP(notshown).The replacementof the dADPwithdATPor ATP(not shown)then inducesthecomplexof Apafl and cytochromec toaggregateto form a large,heptamericapoptosome,whichthen recruitsprocaspase-9througha caspaserecruitmentdomain(CARD)in eachprotein.The procaspase-9moleculesareactivatedwithin the apoptosomeand arenow able to cleaveand activateprocaspases,downstreamexecutionerwhich leadsto the cleavageand activationof thesemoleculesin a caspasecascade.Otheroroteinsreleasedfrom themitochondrialintermembranespacearenot shown.(B)A modelofthe threedimensionalstructureof an apoptosome.Notethat somescientistsusethe term"apoptosome"toreferto the complex(B,fromcontainingprocaspase-9.D.
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