procaspase

Procaspases are inactive zymogens that serve as the precursors to the caspase proteases, which execute programmed cell death and contribute to inflammation. They are synthesized as single-chain proteins with an N-terminal prodomain, a large catalytic subunit (p20), and a small catalytic subunit (p10). Activation occurs by proteolytic cleavage at specific aspartate residues within activation linkers, producing the large and small subunits that assemble into an active caspase heterotetramer. Initiator procaspases typically contain longer prodomains with death effector domains (DED) or a caspase recruitment domain (CARD) to facilitate recruitment to activation platforms such as the DISC or the apoptosome, whereas executioner procaspases have short prodomains and are activated by cleavage from initiator caspases.

In the intrinsic (mitochondrial) pathway, cytochrome c release leads to formation of the apoptosome and activation of initiator procaspase-9. In the extrinsic (death receptor) pathway, adaptor proteins recruit initiator procaspases such as procaspase-8 or -10 to the DISC. Once activated, initiator caspases cleave and activate executioner procaspases, such as procaspase-3 and procaspase-7, which then execute apoptosis by proteolytically processing a broad set of cellular substrates.

Regulation of procaspase activation is tightly controlled by cellular factors, including inhibitors of apoptosis (IAPs) and FLIP proteins, and by post-translational modifications. Dysregulation of procaspase activation is linked to disease: insufficient activation can contribute to cancer by allowing cells to evade apoptosis, whereas excessive activation can contribute to neurodegenerative and inflammatory conditions.