Caspase Activation and Inhibition

Executioner caspases, when activated, cleave hundreds or thousands of substrates in the cell to orchestrate apoptosis. In most animals, the executioner caspases have short prodomains lacking interaction sites for other proteins (the exception, as we have noted in Green (2022a), is in nematodes, which have an executioner caspase with a long, interactive prodomain). The inactive forms (or "proforms") of these caspases exist in the cell as dimers, with the potential to form two active sites. These are constrained from forming their active sites until they are cleaved between the large and small subunits. This cleavage permits the chain-chain interaction that snaps the two active sites into place, allowing the now-mature protease to be maximally functional. This is an important rule for understanding apoptosis that bears repeating: