Procaspase9

Procaspase-9 is the zymogen form of caspase-9, a cysteine protease that functions as an initiator caspase in the intrinsic (mitochondrial) pathway of apoptosis. It is synthesized as an inactive proenzyme containing an N-terminal caspase activation and recruitment domain (CARD) and a C-terminal catalytic domain.

Activation occurs when cellular stress causes mitochondrial outer membrane permeabilization and cytochrome c release. Cytochrome c binds to Apaf-1 in the presence of dATP/ATP to form the apoptosome. Procaspase-9 is recruited to the apoptosome via CARD–CARD interactions with Apaf-1, bringing molecules into proximity to promote autocatalytic processing. This processing yields the active caspase-9 heterotetramer, typically composed of p35 and p12 subunits, which can then cleave and activate downstream executioner caspases such as caspase-3 and caspase-7.

Regulation of procaspase-9 activity occurs at several levels. The apoptosome-dependent recruitment is a critical control point, and mature caspase-9 activity can be inhibited by inhibitors of apoptosis proteins (IAPs) such as XIAP, which bind to active caspase-9 and block substrate access. Additional regulation may involve post-translational modifications and alternative splice forms that influence activation or signaling efficiency.

In broad terms, procaspase-9 and its activation within the apoptosome link mitochondrial distress signals to the execution phase of apoptosis. Dysregulation of this pathway has been associated with various diseases, including cancer and neurodegenerative disorders, making the procaspase-9–apoptosome axis a focus of research into therapeutic modulation of cell death.