apoptosome

The apoptosome is a large cytosolic protein complex that activates initiator caspases in the intrinsic pathway of apoptosis. It forms in response to mitochondrial outer membrane permeabilization and the release of cytochrome c into the cytosol. Assembly requires cytochrome c and the nucleotide dATP or ATP.

The core components are Apaf-1 (apoptotic protease activating factor 1), cytochrome c, and procaspase-9. Apaf-1 contains an N-terminal caspase recruitment domain (CARD), a central nucleotide-binding and oligomerization domain (NB-ARC), and C-terminal WD40 repeats that bind cytochrome c. Upon cytochrome c binding and nucleotide exchange, Apaf-1 undergoes a conformational change and oligomerizes into a heptameric wheel-like apoptosome. This platform recruits procaspase-9 through CARD–CARD interactions, promoting its activation via proximity-induced autoproteolysis.

Active caspase-9 then cleaves and activates effector caspases such as caspase-3 and caspase-7, triggering the proteolytic cascade that leads to apoptotic cell death. The apoptosome thus serves as a critical signaling hub that converts mitochondrial distress into a committed cell death program. Its activity is tightly regulated, and its dysregulation is associated with various diseases, including cancer and neurodegenerative disorders, where apoptotic execution may be altered or suppressed.