The protein structures that shape caspase activity, specificity, activation and inhibition

Area of Science:

• Molecular Biology
• Biochemistry
• Structural Biology

Background:

• Apoptosis, or programmed cell death, is a critical biological process regulated by specific limited proteolysis.
• Significant advancements in understanding the structural basis of apoptosis regulation have been made in the last decade.
• The field now possesses substantial structural data covering various stages of apoptosis, including initiators, regulators, executioners, inhibitors, and substrates.

Purpose of the Study:

• To provide a comprehensive review of caspases, their regulators, and inhibitors.
• To consolidate structural and mechanistic insights into the rapidly growing field of apoptosis.
• To highlight the therapeutic potential of understanding apoptosis regulation for degenerative diseases and cancer.

Main Methods:

• Review of existing structural and mechanistic data on caspases, their regulators, and inhibitors.
• Analysis of fundamental protease regulation mechanisms.
• Examination of the structural basis for caspase activation and inhibition strategies.

Main Results:

• The structural understanding of apoptosis regulation is now comparable to well-established proteolytic pathways like the coagulation cascade.
• Novel mechanisms in protease regulation and unusual catalytic mechanisms for caspases have been disclosed.
• Both classic and novel inhibition strategies employed by natural caspase inhibitors have been identified.

Conclusions:

• Structural and mechanistic knowledge of apoptosis pathways is rapidly advancing.
• Caspase activation and inhibition involve diverse and sometimes unexpected mechanisms.
• This knowledge is directly applicable to developing therapeutics for diseases characterized by aberrant apoptosis.