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Molecular ordering of apoptotic mammalian CED-3/ICE-like proteases
K Orth1, K O'Rourke, G S Salvesen
1Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Abstract:
Apoptosis is executed by cysteine proteases belonging to the CED-3/ICE family, which, unlike other mammalian cysteine proteases, cleave their substrates following aspartate residues. Proteases belonging to this family exist in the cytosol as zymogens that require accurate processing at internal aspartate residues to generate the two-chain active enzymes. As such, CED-3/ICE family members are capable of activating each other in a manner analogous to the protease zymogens of the coagulation or complement cascades. At present, it is unknown whether such mutual processing exists in vivo, and if so whether it is sequential, implying an order to the death pathway. Using a cell-free apoptosis system, recombinant ICE proteases and both biochemical and morphological criteria, we demonstrate an ordering of the mammalian ICEs that are most related to the Caenorhabditis elegans death protease CED-3.
Insights
This study reveals a sequential activation order for mammalian ICE proteases, key executioners of apoptosis. This finding helps elucidate the molecular cascade of programmed cell death.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Apoptosis, or programmed cell death, is executed by CED-3/ICE family cysteine proteases.
- These proteases cleave substrates after aspartate residues and exist as zymogens requiring processing for activation.
- Mammalian ICE proteases may activate each other, similar to coagulation or complement cascades, but in vivo order is unknown.
Purpose of the Study:
- To investigate the potential for mutual processing and sequential activation among mammalian ICE proteases.
- To establish an order for the activation pathway of ICE proteases related to Caenorhabditis elegans CED-3.
Main Methods:
- Utilized a cell-free apoptosis system.
- Employed recombinant ICE proteases.
- Applied biochemical and morphological criteria for analysis.
Main Results:
- Demonstrated a specific ordering of mammalian ICE protease activation.
- Provided evidence for a sequential cascade in ICE protease-mediated apoptosis.
- Linked mammalian ICE proteases to the function of C. elegans CED-3.
Conclusions:
- Established a sequential activation order for mammalian ICE proteases.
- The findings suggest a defined molecular pathway for apoptosis execution.
- This research clarifies the hierarchical activation of proteases involved in programmed cell death.