Procaspasen

Procaspases are inactive precursors of caspases, a family of cysteine proteases that play central roles in programmed cell death and inflammatory signaling. In humans, caspases are produced as zymogens called procaspases that comprise an N-terminal prodomain, a large catalytic subunit p20, and a small catalytic subunit p10. The active site contains a catalytic cysteine within a conserved motif, typically QACRG, which forms a cysteine–histidine dyad in the mature enzyme.

Activation occurs through proteolytic processing. Initiator procaspases, which have long prodomain regions containing death effector domains (DED) or a caspase activation and recruitment domain (CARD), are recruited to signaling complexes such as the death-inducing signaling complex (DISC) at extrinsic death receptors or the apoptosome in the intrinsic pathway. They are cleaved to form active initiator caspases, which subsequently activate executioner procaspases (with short prodomain), producing mature enzymes that execute apoptosis by cleaving cellular substrates such as PARP and ICAD. The resulting active caspases assemble as heterotetramers of large and small subunits.

Procaspase activity is tightly regulated by inhibitors of apoptosis (IAPs), FLIP proteins, and various post-translational modifications. In addition to apoptosis, several caspases participate in nonapoptotic processes, including inflammation for caspases with inflammatory roles.

Dysregulation of procaspase activation is associated with diseases such as cancer, neurodegenerative disorders, and immune dysfunction. Understanding procaspase activation provides insight into cell fate decisions and offers potential targets for therapeutic intervention.