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Review
. 1999 Apr;1(1):5-15.
doi: 10.1038/sj.neo.7900003.

The apoptosome: heart and soul of the cell death machine

A M Chinnaiyan  1
Affiliations
Review

The apoptosome: heart and soul of the cell death machine

A M Chinnaiyan. Neoplasia. 1999 Apr.

Abstract

Apoptosis is a fundamental biologic process by which metazoan cells orchestrate their own self-demise VSports手机版. Genetic analyses of the nematode C elegans identified three core components of the suicide apparatus which include CED-3, CED-4, and CED-9. An analogous set of core constituents exists in mammalian cells and includes caspase-9, Apaf-1, and bcl-2/xL, respectively. CED-3 and CED-4, along with their mammalian counterparts, function to kill cells, whereas CED-9 and its mammalian equivalents protect cells from death. These central components biochemically intermingle in a ternary complex recently dubbed the "apoptosome. " The C elegans protein EGL-1 and its mammalian counterparts, pro-apoptotic members of the bcl-2 family, induce cell death by disrupting apoptosome interactions. Thus, EGL-1 may represent a primordial signal integrator for the apoptosome. Various biochemical processes including oligomerization, adenosine triphosphate ATP/dATP binding, and cytochrome c interaction play a role in regulating the ternary death complex. Recent studies suggest that cell death receptors, such as CD95, may amplify their suicide signal by activating the apoptosome. These mutual associations by core components of the suicide apparatus provide a molecular framework in which diverse death signals likely interface. Understanding the apoptosome and its cellular connections will facilitate the design of novel therapeutic strategies for cancer and other disease states in which apoptosis plays a pivotal role. .

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Figures

Figure 1
Figure 1
The apoptosome: A molecular framework for cell death C elegans (left) and mammals (right). In C elegans, CED-4 plays a crucial role as a molecular death switch, interacting with and assisting in the activation of the latent death protease CED-3. CED-9 presumably interacts with and negatively regulates CED-4 function. EGL-1 can disrupt the apoptosome by sequestering CED-9. With some added complexity, this primordial paradigm is likely recapitulated in mammals. Unlike C elegans, the mammalian death machinery is complicated by redundancy. Bcl-xl, bcl-2, and other death suppressors of the bcl-2 family inhibit apoptosis by negatively regulating Apaf-1. By contrast, death-promoting members of the bcl-2 family such as bid, bik, and bad antagonize the interactions between bcl-2/xl and Apaf-1. In the absence of negative regulation, Apaf-1 is free to engage and activate the death protease, caspase-9. Cytochrome c and ATP/dATP likely function as cofactors for the apoptosome. Once triggered, apical caspases such as caspase-9 activate downstream small prodomain caspases.
Figure 2
Figure 2
Schematic representation of apoptosome constituents.
Figure 3
Figure 3
The C elegans apoptosome and its mechanism of activation. In the inactive state the ternary complex (CED-3, CED-4, and CED-9) is assembled on mitochondria. An unspecified death signal mobilizes EGL-1. In turn, EGL-1 binds CED-9, disengaging the apoptosome. CED-4 proceeds to oligomerize and induce the proximity and consequent activation of proCED-3 molecules.
Figure 4
Figure 4
The mammalian apoptosome and its interface with the CD95 pathway. 1: Unactivated CD95(Fas/APO-1) expressed on the cell surface. DD, death domain. DED, death effector domain. 2: Formation of the CD95 death-signaling complex after trimerization by CD95L. Initially, the death adaptor FADD is recruited the cytoplasmic domain of CD95. FADD in turn induces proximity among procaspase-8 molecules, leading to 3: proteolytic activation. 4: Active caspase-8 then cleaves small-prodomain caspases, leading to cell death. 5: Alternatively, caspase-i can cleave the bcl-2 homologue Bid. 6: Once Bid is proteolytically cleaved to tBid (truncated) it can bind bcl-xl. In the inactive state (A), Apaf-1 is in a closed conformation bound to bcl-xl. The asterisk represents the P-loop motif. CARD, caspase recruitment domain. Upon death stimulus, cytochrome c is released from mitochondria (B). Likewise, death signals mobilize proapoptotic members of the bcl-2 family, such as Bid, to disrupt the latent apoptosome (C). Cytochrome c and/or dATP/ATP hydrolysis induces a conformational change in Apaf-1, negating the inhibitory effect of the WD-40 repeats (black boxes in the Apaf-1 molecule). In the open conformation and liberated of bcl-xl inhibition, Apaf-1 is free to self-associate via its CED-4-like domain (D). CARD-CARD associations link Apaf-1 to procaspase-9. Oligomerization of Apaf-1 aggregates procaspase-9, leading to its proteolytic activation (E) and consequent induction of cell death.
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