CASP3 Protein — Caspase-3

CASP3 Protein — Caspase-3

Introduction

Casp3 Protein — Caspase 3 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

CASP3 Protein — Caspase-3

Introduction

Casp3 Protein — Caspase 3 is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

<div class="infobox infobox-protein"> [@supsup2003]
<h3>CASP3 Protein</h3>
<table>
<tr><th>Protein Name</th><td>Caspase-3</td></tr>
<tr><th>Gene</th><td>[CASP3](/genes/casp3)</td></tr>
<tr><th>UniProt ID</th><td>[P42574](https://www.uniprot.org/uniprot/P42574)</td></tr>
<tr><th>Protein Size</th><td>277 amino acids (active enzyme); full-length pro-Caspase-3 is 320 aa (~35 kDa)</td></tr>
<tr><th>Subcellar Localization</th><td>Cytoplasm; cleaves substrates in both cytosol and nucleus</td></tr>
<tr><th>Protein Family</th><td>Cysteine-aspartic proteases (caspases); executioner caspases</td></tr>
<tr><th>PDB Structures</th><td>[1CP3](https://www.ebi.ac.uk/pdbe/search/pdb/1CP3), [1R2X](https://www.ebi.ac.uk/pdbe/search/pdbX/1R2), [2J30](https://www.ebi.ac.uk/pdbe/search/pdb/2J30)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">833 edges</a></td>
</tr>
</table>
</div>

Caspase-3 is the primary executioner caspase in the [apoptosis](/entities/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.

Structure

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

Normal Function

Caspase-3 performs critical functions in:

• Synaptic plasticity and memory (low-level activation)
• Cellular differentiation
• Inflammation (limited roles)

Role in Disease

Alzheimer's Disease

Caspase-3 activation is a hallmark of AD [neurons](/entities/neurons):

• Cleaves [tau](/proteins/tau), generating neurotoxic fragments that form tangles^[2]
• Cleaves [APP](/entities/app-protein), generating amyloidogenic fragments
• Mediates [amyloid-beta](/proteins/amyloid-beta)-induced neuronal apoptosis
• Activated caspase-3 cleaved tau (c-tau) is a potential biomarker

Parkinson's Disease

Caspase-3 contributes to dopaminergic neuron death:

• Mediates MPTP-induced parkinsonism
• Activated in Lewy bodies and surrounding neurons
• Cleaves [α-synuclein](/proteins/alpha-synuclein), generating aggregation-prone fragments

Amyotrophic Lateral Sclerosis (ALS)

Caspase-3 activation in motor neurons:

• Elevated in ALS spinal cord and motor [cortex](/brain-regions/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

Therapeutic Targeting

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

Interactions

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

Pathway & Interaction Diagram

Interactive diagram showing CASP3 key relationships in the SciDEX knowledge graph (15 connections shown).

See Also

• [CASP3 Gene](/genes/casp3)
• [Apoptosis Pathways](/mechanisms/apoptosis-pathways)
• [Alzheimer's Disease Mechanisms](/mechanisms/alzheimers-pathogenesis)
• [Caspase Cascade](/mechanisms/caspase-cascade)
• [PARP and Neurodegeneration](/proteins/parp1-protein)

Background

The study of Casp3 Protein — Caspase 3 has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/) - Biomedical literature
• [Alzheimer's Disease Neuroimaging Initiative](https://adni.loni.usc.edu/) - Research data
• [Allen Brain Atlas](https://brain-map.org/) - Brain gene expression data

References

PMID: 17636039(https://pubmed.ncbi.nlm.nih.gov/17636039/) PMID: 12651865(https://pubmed.ncbi.nlm.nih.gov/12651865/)