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Caspases in apoptotic death
1Texas Biotechnology Corporation, 7000 Fannin, Houston, TX 77030, USA.
Abstract:
Caspases are the central mediators of normal and pathological apoptotic death. They are cysteine proteases that cleave after aspartic acid. The inactive pro-enzymes are proteolytically processed and activated through mechanisms of recruitment to signalling complexes, upstream activator caspases or autoactivation. Many amplifying cascades exist in caspase activation pathways that are evolutionarily conserved. The human caspase family contains at least 10 members which form 3 groups based on substrate specificity, proteolytic targets and functional actions. The crystal structure has been solved for members from two of these groups with inhibitory peptides bound in the active site. These structures have allowed tremendous insight into mechanisms of catalysis, substrate binding and substrate specificity. Enlightened knowledge of enzyme-substrate interactions has led to the design of many inhibitors that are active in animal models of caspase-mediated cell death. Testing in animal models should lead to drugs for therapeutic intervention in the many human diseases characterised by excessive apoptotic cell death.
Insights
Caspases, crucial proteases in cell death, are activated through complex signaling pathways. Understanding their structure and function enables the development of inhibitors for diseases involving excessive apoptosis.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Caspases are cysteine proteases central to apoptosis, cleaving after aspartic acid residues.
- Their activation involves proteolytic processing and recruitment into signaling complexes, often through amplifying cascades.
Purpose of the Study:
- To elucidate the structural basis of caspase activity and substrate specificity.
- To explore the potential of caspase inhibitors for therapeutic applications in diseases with excessive apoptotic cell death.
Main Methods:
- Analysis of crystal structures of human caspase family members with bound inhibitory peptides.
- Investigating enzyme-substrate interactions and their implications for inhibitor design.
Main Results:
- Crystal structures revealed detailed mechanisms of catalysis, substrate binding, and specificity within two caspase groups.
- Inhibitors designed based on structural insights demonstrated activity in animal models of caspase-mediated cell death.
Conclusions:
- Structural biology provides critical insights into caspase function and substrate interactions.
- Caspase inhibitors hold promise for therapeutic interventions in various human diseases characterized by excessive apoptosis.
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01:30Apoptosis
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01:30Overview of Cell Death
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