10 Questions
What is the specific residue that caspases prefer to cleave proteins after?
Aspartate
What type of domains do initiator procaspases possess that mediate homophilic interactions?
Death-effector domain (DED) and caspase-recruitment domain (CARD)
What is the role of the short prodomain in executioner procaspases?
It inhibits the executioner procaspase
What is the product of the cleavage of procaspase-3 by initiator caspases?
A large subunit, a small subunit, and a short inhibitory prodomain
What is the consequence of MOMP?
The escape of villainous proteins from the mitochondrial intermembrane space
What is the primary function of the antiapoptotic members of the BCL-2 family?
To counteract proapoptotic proteins
Which BCL-2 homology domain is necessary for the killing action of proapoptotic members?
BH3
What is the role of the C-terminal hydrophobic domain (TM) in BCL-2 family members?
To aid association with intracellular membranes
What occurs during autophagy in terms of LC3 processing?
LC3 is conjugated to phosphatidylethanolamine to form LC3-II
What is the outcome of autophagosomes fusing with lysosomes?
Degradation of targets by lysosomal proteases
Study Notes
Caspases – Initiators and Executioners of Apoptosis
- Caspases are highly selective cysteine proteases that preferentially cleave proteins after aspartate residues (Asp).
- Initiator procaspases (e.g., procaspase-8 and procaspase-9) have long prodomains containing protein interaction domains (e.g., DED and CARD), which mediate homophilic interactions with adaptor proteins (e.g., APAF-1 and FADD).
- Executioner procaspases (e.g., procaspase-3) have short prodomains that inhibit caspase activation.
- Procaspase-3 is activated by initiator caspases, involving cleavage at specific Asp residues, yielding a short inhibitory prodomain, a large subunit (p20), and a small subunit (p10).
- The activated p20 and p10 subunits form a heterodimer, which associates with another heterodimer to form a proteolytic tetramer.
Mitochondrial Outer Membrane Permeabilization (MOMP) and the BCL-2 Family
- MOMP is a key activator of caspases and cell death, allowing the release of pro-apoptotic proteins (e.g., cytochrome c) from the mitochondrial intermembrane space.
- The BCL-2 family of proteins regulates MOMP, comprising antiapoptotic (cell survival), proapoptotic (apoptosis), and "BH3-only" (proapoptotic) members.
- BCL-2 family members possess at least one of four conserved motifs (BH1-BH4) and a C-terminal hydrophobic domain (TM) for membrane association.
- During apoptosis, proapoptotic BCL-2 family members undergo a conformational change, exposing the BH3 domain, necessary for their killing action.
Regulation of Mitochondrial Outer Membrane Permeabilization (MOMP)
- The BCL-2 family regulates MOMP, counteracting proapoptotic proteins (e.g., BAX and BAK) that promote apoptosis.
- p53, a tumor suppressor, also regulates apoptosis in response to DNA damage.
Autophagy
- Autophagy is a complex process involving the formation of autophagosomes, which engulf cytoplasmic components, including proteins and organelles.
- Microtubule-associated protein 1A/1B-light chain 3 (LC3) is conjugated to phosphatidylethanolamine, forming LC3-II, which is recruited to autophagosomal membranes.
- Autophagosomes fuse with lysosomes to form autolysosomes, where captured components are degraded by lysosomal proteases.
Learn about caspases, highly selective cysteine proteases that play a crucial role in initiating and executing apoptosis. Understand the structure and function of initiator and executioner caspases.
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