DIABLO (Direct IAP Binding protein with Low pI) also known as Smac (Second mitochondria-derived activator of caspases) is a mitochondrial protein released during apoptosis that neutralizes Inhibitor of Apoptosis Proteins (IAPs), enabling caspase activation and cell death. In neurons, DIABLO release is a critical commitment point in the intrinsic apoptosis pathway triggered by various neurodegenerative disease mechanisms.
| Property |
Value |
| Gene |
DIABLO |
| UniProt ID |
Q9NR28 |
| PDB Structures |
1FEW, 1G73, 2NS1 |
| Molecular Weight |
~25 kDa (precursor), ~12 kDa (mature dimer) |
| Subcellular Localization |
Mitochondrial intermembrane space, cytosol (after release) |
| Protein Family |
IAP antagonist family |
DIABLO is synthesized as a precursor with:
- N-terminal mitochondrial targeting sequence (MTS): Directs import into mitochondria
- Internal dimerization domain: Forms functional homodimers
- IAP-binding motif (IBM): N-terminal tetrapeptide (AVPI) that binds IAPs
- C-terminal helix: Important for dimer formation and membrane interaction
The mature DIABLO forms a homodimer that binds multiple IAP molecules simultaneously.
- Apoptosis amplification: Released from mitochondria following outer membrane permeabilization (MOMP)
- IAP neutralization: Binds to IAPs (cIAP1, cIAP2, XIAP) and blocks their caspase-inhibitory function
- Caspase activation: Enables full activation of caspase-3, -7, and -9
- Non-apoptotic signaling: May have roles in mitochondrial quality control
- Mitochondrial dysfunction: Aβ triggers mitochondrial permeability transition and DIABLO release
- Neuronal apoptosis: DIABLO release contributes to neuron loss in AD brain
- Caspase activation: Activates executioner caspases in AD-affected neurons
- Mitochondrial toxins: MPTP, rotenone, and 6-OHDA trigger DIABLO release
- Dopaminergic neuron death: DIABLO-mediated apoptosis contributes to PD pathogenesis
- PINK1/Parkin: May intersect with mitophagy pathways
- SOD1 mutants: Mutant SOD1 causes mitochondrial dysfunction and DIABLO release
- Motor neuron apoptosis: DIABLO contributes to caspase activation in ALS
- Energy failure: Mitochondrial dysfunction triggers DIABLO release
- mHtt effects: Mutant huntingtin causes mitochondrial dysfunction and DIABLO release
- Transcriptional dysregulation: Alters DIABLO expression in HD models
- IAP agonists: Mimic DIABLO function to promote cell death in cancer (contrary for neurodegeneration)
- Caspase inhibitors: Block downstream execution
- Mitochondrial stabilization: Prevent DIABLO release from mitochondria
- IAP enhancement: Increase XIAP or cIAP levels to block DIABLO
- Antiapoptotic proteins: Bcl-2 family overexpression to prevent MOMP