caspasa9

Caspase-9 is a human cysteine protease that functions as an initiator caspase in the intrinsic pathway of apoptosis. It is encoded by the CASP9 gene.

Structure and activation: Caspase-9 is synthesized as a zymogen, procaspase-9, of about 46 kDa, containing an N-terminal caspase activation and recruitment domain (CARD) that mediates interactions with the apoptosome. In response to mitochondrial stress, cytochrome c is released into the cytosol and, together with Apaf-1 and dATP/ATP, forms the apoptosome. Procaspase-9 is recruited to the complex via CARD–CARD interactions and undergoes autocatalytic processing to generate the active heterotetramer composed of p35 and p12 subunits. Activated caspase-9 then cleaves and activates executioner caspases such as caspase-3 and caspase-7.

Regulation: Activity is controlled by inhibitors of apoptosis proteins (IAPs), notably XIAP, which can bind and inhibit active caspase-9. Phosphorylation and other post-translational modifications can modulate its activity. Alternative splicing can produce caspase-9S, a catalytically inactive isoform that can act as a dominant negative regulator of apoptosis.

Clinical and research notes: Caspase-9 plays a central role in programmed cell death, and dysregulation is associated with cancer, neurodegenerative diseases, and immune disorders. It is a focus of research into therapies that modulate apoptosis, including strategies to promote cell death in cancer or to prevent excessive cell loss in degenerative conditions.