Apoptosome

The apoptosome is a quaternary protein structure formed in the process of apoptosis. It is formed by the release of cytochrome c from the mitochondrion responses to an internal (intrinsic) or external (extrinsic) cell death stimulus. Stimuli can differ from DNA damage or viral infection to developmental signals for instance like those leading to the degradation of a tadpole’s tail.

When cytochrome c is released, it binds to the cytosolic protein Apoptotic protease activating factor-1 (Apaf-1) to facilitate the formation of the apoptosome in mammalian cells. Biochemical and structural studies have shown that this interaction is essential for apoptosome assembly. Additionally, the nucleotide dATP binds to Apaf-1 as a third component, although its precise role in the process remains under investigation.

The mammalian apoptosome had never been crystallized, but a human Apaf-1/cytochrome-c apoptosome has been imaged at lower (2 nm) resolution by cryogenic transmission electron microscopy in 2002, showing a heptameric wheel-like particle with 7-fold symmetry. Recently, a medium resolution (9.5 Ångström) structure of human apoptosome was also solved by cryo-electron microscopy, which allows unambiguous inference for positions of all the Apaf-1 domains (CARD, NBARC and WD40) and cytochrome c. A crystal structure of the monomeric, inactive Apaf-1 subunit (PDB 3SFZ) is currently obtainable. Following its formation, the apoptosome can then recruit and activate the inactive pro-caspase-9. Once activated, this initiator caspase can then activate effector caspases and trigger a cascade of events leading to apoptosis.