Molecular and Biological Aspects of Apoptosis - Execution: role of caspases
8 important questions on Molecular and Biological Aspects of Apoptosis - Execution: role of caspases
What are the general features of proteases?
- Proteolysis is irreversible
- Proteases are synthesized as precursors and can be activated by autokatalysis or other proteases
- Proteases can regulate their activity by an amplificationloop resulting in a fast activation (cascade)
- Proteases can be inhibited by protease inhibitors, increasing the threshold and prevent spontaneous activation.
- Are very substrate specific
Activation of procaspase 8 by autocleavage
What effect does FLIP have on the activity of procaspase 8?
- Caspase-8 is normally involved in the activation of the RIPK1 and RIPK3 complex (necrosome).
- High levels of FLIP inhibit caspase-8 resulting in cell survival.
- FLIP also prevents the formation of the necrosome
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How do caspases disassemble a cell?
- Inactivation of inhibitors of apoptosis
- Disassembly of cell structures
- Deregulation of protein activity
How does the activation of procaspase 1 induce inflammation?
- Signal 1: PAMPs/DAMPs bind to TLRs and activate NF-kB, which promotes the transcription of NLRP3, proIL-b and proIL-18.
- A stimulus will activate NLRP3 inflammasome by facilitating the oligomerization of NLRP3, ASC and procaspase-1.
- This complex catalyzes the conversion of procaspase-1 to caspase-1, which contributes to the production and secretion of mature IL-1B and IL-18.
Caspase-1 may also induce pyroptosis
When this is cleaved, it will form pores releasing inflammatory factors. The cell will swell and die in a necrotic way because water will enter the cell.
What are inhibitors of caspases?
The regions can bind Smac/DIABLO to prevent inhibition of the caspase.
Interaction of caspase-3 and caspase-9 with XIAP
- BIR domains can bind and inhibit caspase-9
- When Smac/DIABLO is expressed it binds to the same region, making the caspase active.
- The same for caspase-3 and caspase-7
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