BCH3042 Lecture Notes - Lecture 14: Caspase, Apoptosis, Cytochrome C
25 May 2018
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Lecture 14 – Cell Death
Types of Cell Death
• Apoptosis: program of cell death (1)
o Get nuclear fragmentation
• Necrosis: accidental cell death (2)
Apoptosis vs. Necrosis
How Caspases are Activated
• BH3 only proteins, pro survival BCL-2 proteins and BAX and BAK → cause
mitochondria to release cytochrome C → releases caspase 9 → effector
caspases
• Caspases = cysteine aspartic acid proteases
o Cys at active site (reactive nucleophile)
o Cleave substrates after Aspartic acid (D)
▪ Cleavage causes small (~10kDa) and large (~20kDa) subunit
(p20/p10)
o Form dimers of heterodimers (i.e. 20/10-20/10)
• 15 in mammals (not all in apoptosis)
• Present in cytosol and nucleus
• Some caspases not involved in apoptosis
• Caspases are activated in a cascade
o Initiator caspases: activated by oligomerisation, recognise effector
caspases as substrates
o Effector caspases: cleave cellular substrates
• Active Caspases
o Cleavage to make large (L2) and small subunits (L2’)
▪ Red loop: where substrates bind
▪ Yellow: inhibitor
▪ L2’ interacts with L2 of other subunit and stabilises the
catalytic groove in the adjacent monomer
Cell Clearance – controlled demolition of the cell
• Condensation of nucleus and its fragmentation
• Loss of cell attachment to substrate
Apoptosis
Necrosis
• Get dead cell bodies
• Don’t get inflammatory response
• Need to kill cells for development
• Signals that elicit apoptosis
o Inside the cell (suicide)
▪ E.g. DNA damage,
oxidative stress,
cytosolic calcium
overload
o Outside the cell (murder)
▪ E.g. death signals
from other cells (death
ligands)
• Unregulated
• Mitochondria swells →
inflammatory response
• Necrotic cells trigger
inflammation by cells of innate
immune system e.g. neutrophils,
macrophages
• Stimulated by release of danger
associated molecular patterns
(DAMPs)
• Pathogens stimulate necrosis and
trauma provoking necrosis
facilitates infection
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