Caspases, which are the executioners of apoptosis, comprise two distinct classes, the initiators and the effectors. Although general structural features are shared between the initiator and the effector caspases, their activation, inhibition and release of inhibition are differentially regulated. Biochemical and structural studies have led to important advances in understanding the underlying molecular mechanisms of caspase regulation. This article reviews these latest advances and describes our present understanding of caspase regulation during apoptosis.
Recent work on the initial switches that trigger cell death has revealed surprising inventions of nature that ensure the ordered suicide of a cell that has been selected for demise. Particularly intriguing is how a signal--the release of cytochrome c from the mitochondria--is translated into the activation of the death cascade, which leads to a point of no return. Now there is new understanding of how this crucial process is delicately handled by a cytosolic signalling platform known as the apoptosome. The formation of the apoptosome and the activation of its effector, caspase-9, reveals a sophisticated mechanism that might be more common than was initially thought.
The inhibitor of apoptosis (IAP) proteins potently inhibit the catalytic activity of caspases. While profound insight into the inhibition of the effector caspases has been gained in recent years, the mechanism of how the initiator caspase-9 is regulated by IAPs remains enigmatic. This paper reports the crystal structure of caspase-9 in an inhibitory complex with the third baculoviral IAP repeat (BIR3) of XIAP at 2.4 A resolution. The structure reveals that the BIR3 domain forms a heterodimer with a caspase-9 monomer. Strikingly, the surface of caspase-9 that interacts with BIR3 also mediates its homodimerization. We demonstrate that monomeric caspase-9 is catalytically inactive due to the absence of a supporting sequence element that could be provided by homodimerization. Thus, XIAP sequesters caspase-9 in a monomeric state, which serves to prevent catalytic activity. These studies, in conjunction with other observations, define a unified mechanism for the activation of all caspases.
The Death Inducing Signaling Complex (DISC) formed by Fas receptor, FADD and caspase-8 is a pivotal trigger of apoptosis1-3. The Fas/FADD DISC represents a receptor platform, which once assembled initiates the induction of programmed cell death. A highly oligomeric network of homotypic protein interactions comprised of the death domains (DD) of Fas and FADD is at the center of DISC formation4, 5. Thus characterising the mechanistic basis for the Fas/FADD interaction is paramount for understanding DISC signaling but has remained enigmatic largely due to a lack of structural data. We have successfully formed and isolated the Fas/FADD DD complex and here we report the 2.7 Å crystal structure. The complex shows a tetrameric arrangement of four FADD DDs bound to four Fas DDs. We show that an opening of the Fas DD exposes the FADD binding site and simultaneously generates a Fas/Fas bridge. The result is a regulatory Fas/FADD complex bridge governed by weak protein:protein interactions revealing a model where the complex functions as a mechanistic switch. This switch prevents accidental DISC assembly, yet allows for highly processive DISC formation and clustering upon a sufficient stimulus. Thus besides depicting a previously unknown mode of death domain interactions, these results further uncover a mechanism for receptor signaling solely by oligomerization and clustering events.
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