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Caspase activation: the induced-proximity model
1Programs in Cell Death and Aging Research, Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. gsalvesen@burnham-inst.org
Abstract:
Members of the caspase family of proteases transmit the events that lead to apoptosis of animal cells. Distinct members of the family are involved in both the initiation and execution phases of cell death, with the initiator caspases being recruited to multicomponent signaling complexes. Initiation of apoptotic events depends on the ability of the signaling complexes to generate an active protease. The mechanism of activation of the caspases that constitute the different apoptosis-signaling complexes can be explained by an unusual property of the caspase zymogens to autoprocess to an active form. This autoprocessing depends on intrinsic activity that resides in the zymogens of the initiator caspases. We review evidence for a hypothesis-the induced-proximity model-that describes how the first proteolytic signal is produced after adapter-mediated clustering of initiator caspase zymogens.
Insights
Initiator caspases, crucial for apoptosis, activate through self-processing within signaling complexes. The induced-proximity model explains this activation via adapter-mediated clustering of caspase zymogens.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Biology
Background:
- Caspases are key proteases regulating apoptosis in animal cells.
- Initiator caspases are recruited to signaling complexes to trigger cell death.
- Caspase activation involves autoprocessing of inactive zymogen forms.
Purpose of the Study:
- To review evidence supporting the induced-proximity model for initiator caspase activation.
- To explain the mechanism of protease generation in apoptosis signaling complexes.
Main Methods:
- Review of existing literature and experimental evidence.
- Analysis of the autoprocessing mechanism of caspase zymogens.
- Examination of adapter-mediated clustering in signaling complexes.
Main Results:
- Initiator caspases possess intrinsic activity enabling autoprocessing.
- Adapter proteins facilitate the clustering of initiator caspase zymogens.
- Clustering induces proximity, leading to the generation of active caspases.
Conclusions:
- The induced-proximity model provides a framework for understanding initiator caspase activation.
- Autoprocessing of clustered zymogens is the primary mechanism for initiating the proteolytic cascade in apoptosis.
- This mechanism ensures the precise and timely execution of programmed cell death.