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.…
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.
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Q1: What are caspases and how do they function in cells?
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.
Q2: What is the difference between initiator and effector caspases?
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.
Q3: How are caspases activated from their inactive precursor forms?
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.
Q4: What role do caspases play in maintaining cellular homeostasis?
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.
Q5: How do viruses evade caspase-mediated cell death?
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.
Q6: What happens when caspase activity becomes dysregulated in disease?
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.
Q7: What is the evolutionary origin of caspases in cell death pathways?
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.