Molecular and Biological Aspects of Apoptosis - Intrinsic pathway: role of Bcl2 family
10 important questions on Molecular and Biological Aspects of Apoptosis - Intrinsic pathway: role of Bcl2 family
Two mechanisms for the release of caspase-activating proteins from the mitochondria
- Opening of PTP in the inner membrane, increasing osmotic pressure expanding the matrix space. This results in rupture of the outer membrane.
- Opening of channels in the outer membrane resulting in release of cytochrome C into the cytosol
What two things can happen after a death trigger?
- Dysfunction of the mitochondria makes the cell unhappy and die of necrosis.
- Opening of PTP pore in some mitochondria, so a few start to swell but still ATP production. Cytochrome C assembles with Apaf-1 and caspase-9, inducing apoptosis.
Mitochondrial inner membrane permeabilization (MIMP)
- BCL-2 bound to PTPC will leave it inactive.
- BH3 binding to BCL-2 will result in active PTPC, allowing for the influx of small solutes into the mitochondrial matrix.
- BAX binding to PTPC will also result in solute influx
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Mitochondrial outer membrane permeabilization (MOMP)
- Normal situation: BCL-XL, BCL-2 (anti-apoptotic) and BAK (pro-apoptotic) are on the outer membrane of mitochondria, and BAX and BH3 are cytosolic.
- Upon a trigger, BAX and BAK will undergo conformational changes allowing them to translocate fully into the outer membrane.
- BH3-only proteins can be pro-apoptotic by (1) directly binding to BAX and BAK, or (2) displacing them from inhibitory interactions with BCL-2 or BCL-XL
- Cytotoxic proteins will be released from the mitochondrial intermembrane space (IMS) into the cytosol.
Three subfamilies of Bcl-2 related proteins
- Pro-survival: Bcl2 family with four highly conserved regions (BH1-4)
- Pro-apoptosis: Bax family only three out of four of the regions
- Pro-apoptosis: BH3-only family only the BH3 region
Proapoptotic mitochondrial model
- Bcl2-like proteins guard mitochondrial membrane integrity until neutralized by BH3-only protein.
- Bak and Bax form homo-oligomers resulting in the release of cytochrome C, activating Apaf-1, activating caspase-9.
- Also Omi and Diablo exit the mitochondria antagonizing IAPs.
Different BH3-only proteins
- BIM + PUMA: bind to all homologues
- tBID: bind to all homologues, only weakly to BCL-2
- NOXA: only binds MCL1 and A1
- BAD: only binds BCL-W, BCL-XL and BCL-2
Mechanisms of direct activation model
- Monomeric effector: activation and oligomerization of Bak/Bax.
- Direct activator BH3-only proteins: BIM or BID induce the activation and oligomerization of Bak/Bax in absence of other proteins.
- Repressor BH3-only induction: cannot induce the activation of Bak/Bax alone. Activating BH3-only protein is bound to anti-apoptotic BCL-2 protein. Following stress, sensitizer BH3-only protein will bind to BCL-2 protein, releasing the activating BH3-only protein. Prime of death
- Sensitized for death: sensitizer BH3-only protein are constitutively inhibiting anti-apoptotic BCL-2 proteins.
Death signals that activate BH3-only proteins
Granzyme B cleaving Bid
- Cytotoxic T lymphocyte releases granules into extracellular space containing perforin and granzyme B.
- Granzyme B induces caspase-dependent cell death by cleaving Bid.
- Cleaved Bid interacts with Bak/Bax on mitochondrial membrane.
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