37.3:
Caspases
Cysteine-dependent aspartate-specific proteases, shortened to caspases, are proteases that break down specific cellular proteins and induce apoptosis.
The cysteine residue located in the caspase active site cleaves the peptide bond of the target protein after aspartic acid present at the primary specificity site, or P1 position, in the specific amino acid sequence.
There are two types of apoptotic caspases—initiator caspases and executioner or effector caspases.
Both types of caspases are synthesized as procaspases, the inactive precursors.
Each initiator monomer contains a catalytic domain with large and small subunits and an adaptor-binding domain.
Death signals bring the initiator procaspases close to each other, causing dimerization. The dimerization induces interchain cleavage resulting in the activation of the initiator caspase.
The initiator caspases activate the dimeric effector procaspases by splitting them at the linker region.
The effector caspases then target different cellular proteins, such as cytoskeletal proteins, which eventually results in apoptosis.
37.3:
Caspases
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
Caspase Activation
Caspases are produced as inactive zymogens, called procaspases. The procaspases contain four loops, L1 to L4. During activation, L2 is cleaved, and the monomeric subunits dimerize. The initiator procaspases also have long pro-domains such as the death effector domain (DED) or caspase recruitment domain (CARD). These pro-domains interact with the adaptor molecules to cleave and activate the initiator caspases. Conversely, executioner caspases have short pro-domains and are cleaved by the active initiator caspases.
Caspases and Homeostasis
Cell proliferation and cell death are both essential to maintain homeostasis in multicellular organisms. The over- and under-activation of caspases, thus, can lead to many diseases. For example, decreased caspase activity is a common feature of cancerous cells. Many infectious diseases also decrease caspase activity. For example, the p35 protein released by certain viruses binds the caspases, thus preventing caspase activation and blocking apoptosis. In contrast, the over-activation of inflammatory caspases causes sepsis due to increased inflammatory response. Excessive activation of caspases can also cause diseases such as Alzheimer's, Parkinson’s, and Huntington's.