Kaspazlar

Caspases are cysteine-dependent aspartate-specific proteases that break down specific cellular proteins and induce apoptosis. The cysteine residue in the caspase active site cleaves peptide bonds after aspartic acid at the P1 position in target protein sequences. Beyond apoptosis, caspases also function in inflammatory responses by activating pro-inflammatory cytokines that recruit immune cells and block pathogen replication.

Initiator caspases contain a catalytic domain with large and small subunits plus an adaptor-binding domain, while effector caspases have shorter pro-domains. Death signals cause initiator procaspases to dimerize, triggering interchain cleavage and activation. Active initiator caspases then cleave effector procaspases at the linker region, activating them to target cellular proteins like cytoskeletal proteins.

Caspases are produced as inactive zymogens called procaspases, which contain four loops designated L1 to L4. During activation, L2 is cleaved and monomeric subunits dimerize. Initiator procaspases have long pro-domains such as death effector domains or caspase recruitment domains that interact with adaptor molecules to trigger cleavage and activation.

Cell proliferation and cell death are both essential to maintain homeostasis in multicellular organisms. Decreased caspase activity is common in cancerous cells and certain infectious diseases, where viral proteins like p35 bind caspases and prevent activation. Conversely, over-activation of inflammatory caspases causes sepsis, while excessive caspase activation contributes to neurodegenerative diseases like Alzheimer's and Parkinson's.

Some viruses release proteins like p35 that directly bind to caspases, preventing their activation and blocking apoptosis. This viral strategy allows infected cells to survive longer, enabling pathogen replication. By inhibiting caspase function, viruses can establish persistent infections and evade the immune system's programmed cell death mechanisms.

Dysregulated caspase activity underlies multiple disease states. Under-activation of caspases allows cancerous cells to survive and proliferate unchecked. Over-activation of inflammatory caspases triggers excessive immune responses leading to sepsis. Additionally, uncontrolled caspase activation in neurons contributes to neurodegenerative diseases including Huntington's disease, Parkinson's disease, and Alzheimer's disease.

The ced3 gene in C. elegans was first identified as essential for apoptosis and encodes the ced-3 caspase, which is similar to the interleukin-1-beta converting enzyme (ICE) found in mammals. This evolutionary conservation demonstrates that caspase-mediated apoptosis is a fundamental cell death mechanism preserved across species, from nematodes to humans.