| Protein Name | Caspase-3 |
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| Gene | [CASP3](/genes/casp3) |
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| UniProt ID | P42574 |
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| Protein Size | 277 amino acids (active enzyme); full-length pro-Caspase-3 is 320 aa (~35 kDa) |
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| Subcellar Localization | Cytoplasm; cleaves substrates in both cytosol and nucleus |
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| Protein Family | Cysteine-aspartic proteases (caspases); executioner caspases |
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| PDB Structures | 1CP3, 1R2X, 2J30 |
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Caspase-3 is the primary executioner caspase in the apoptosis pathway, responsible for the proteolytic cleavage of numerous cellular substrates that lead to the characteristic morphological and biochemical features of programmed cell death. It plays a central role in both extrinsic and intrinsic apoptotic pathways.
Caspase-3 has a characteristic caspase structure:
- Prodomain: N-terminal domain (approximately 30-50 residues); short in executioner caspases
- Large Subunit (p17): ~17 kDa, contains the catalytic cysteine residue (C163)
- Small Subunit (p12): ~12 kDa, completes the active site
- Active Site: Conserved pentapeptide motif QACXG (specifically QACRG in CASP3)
- Dimer of Heterodimers: The active enzyme is a dimer of p17/p12 heterodimers
The protease adopts a classic caspase fold with a central six-stranded β-sheet flanked by five α-helices.
Caspase-3 performs critical functions in:
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Apoptosis Execution: Cleaves numerous substrates (~2,000+ known targets) that execute the apoptotic program[1].
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DNA Fragmentation: Cleaves ICAD/DFF45, releasing CAD endonuclease for DNA fragmentation.
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Cytoskeletal Reorganization: Cleaves actin, tubulin, and cytoskeletal proteins for membrane blebbing.
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Membrane Flip: Cleaves flippase inhibitors, exposing phosphatidylserine for phagocytic recognition.
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Cell Cycle Arrest: Cleaves proteins involved in cell cycle progression.
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Non-Apoptotic Functions:
- Synaptic plasticity and memory (low-level activation)
- Cellular differentiation
- Inflammation (limited roles)
Caspase-3 activation is a hallmark of AD neurons:
- Cleaves tau, generating neurotoxic fragments that form tangles[2]
- Cleaves APP, generating amyloidogenic fragments
- Mediates amyloid-beta-induced neuronal apoptosis
- Activated caspase-3 cleaved tau (c-tau) is a potential biomarker
Caspase-3 contributes to dopaminergic neuron death:
- Mediates MPTP-induced parkinsonism
- Activated in Lewy bodies and surrounding neurons
- Cleaves α-synuclein, generating aggregation-prone fragments
Caspase-3 activation in motor neurons:
- Elevated in ALS spinal cord and motor cortex
- Mediates mutant SOD1 toxicity
- Contributes to excitotoxicity-induced cell death
¶ Stroke and Brain Injury
Caspase-3 is the key executor of post-ischemic neuronal death:
- Mediates excitotoxic neuronal injury
- Cleaves PARP-1 in neurons (but not astrocytes)
- Inhibition is neuroprotective in experimental models
Caspase-3 is a major therapeutic target:
- Direct Inhibitors: Peptide-based and small molecule caspase inhibitors (Z-VAD-FMK, DEVD-CHO)
- Irreversible Inhibitors: Electrophilic compounds targeting the active site cysteine
- Activation Modulators: Drugs that prevent caspase activation upstream
- Gene Therapy: Dominant-negative caspase mutants
Note: Broad-spectrum caspase inhibitors have shown neuroprotective effects in animal models but clinical trials have been limited by toxicity and narrow therapeutic windows.
CASP3 interacts with:
- Caspase-8 and Caspase-9: Upstream initiator caspases that activate CASP3
- Apaf-1: In the apoptosome pathway
- XIAP: Inhibitor of apoptosis protein that binds and inhibits CASP3
- PARP-1: Cleaved by CASP3 during apoptosis
- ICAD/DFF45: Cleaved to release CAD endonuclease
- Bid: Cleaved to generate tBid for mitochondrial amplification
- [1] Caspase substrate encyclopedia (Lüthi & Martin, 2007)
- [2] Caspase-3 cleaves tau in Alzheimer's disease (Gamblin et al., 2003)