Apoptosis Pathway

There are two types of apoptosis pathway. The first one is extrinsic apoptosis pathway and the another one is intrinsic apoptosis pathway.

The extrinsic pathway of Apoptosis: Cell-surface Death receptors activate this apoptosis pathway:

1. Death receptors (binds to the extracellular signal proteins) are a transmembrane protein containing an extracellular ligand binding protein (a single transmembrane domain) and an intracellular death domain, which is needed for the receptors to activate the apoptosis pathway.
2. The receptors and the ligands both are homotrimers and belong to the tumor necrosis factor (TNF) receptor family.
3. The activation of Fas on the surface of a target cell by Fas ligand on the surface of a cell (a killer lymphocyte- cytotoxic) is a key procedure of the extrinsic pathway of apoptosis.
4. When activated by the binding of the Fas ligand, the death domains on the cytosolic tails of the Fas death receptors bind intracellular adaptor proteins FADD (Fas-associated death domain), which in turn bind initiator caspases (caspase-8), forming a death-inducing signaling complex (DISC).
5. Once dimerized and activated in the DISC, the initiator caspases cleave their partners and then activate downstream executioner caspases to induce apoptosis.
6. In some cells, the extrinsic pathway recruits the intrinsic apoptotic pathway to amplify the caspase cascade and kill the cell.

The diagram of the extrinsic pathway of apoptosis:

The restriction of the extrinsic pathway of apoptosis:

1. Many cells produce inhibitory proteins that act to restrict the extrinsic pathway of apoptosis.
2. Some cells produce the protein FLIP, which resembles an initiator caspase but has no protease activity because it lacks the key cysteine in its active site.
3. FLIP dimerizes with caspase 8 in the DISC to form an active heterodimer.
4. It is not cleaved at the site required for its stable activation, and the apoptotic signal is blocked.
5. Such inhibitory mechanisms help prevent the inappropriate activation of the extrinsic pathway of apoptosis.

The Intrinsic pathway of apoptosis: Depends on Mitochondria:

1. Cells can activate their apoptosis program from inside the cell, often in response to stresses, such as DNA damage, or in response to the developmental signals.
2. In vertebrate cells, these responses are taken care by the intrinsic pathway of apoptosis or mitochondrial pathway of apoptosis.
3. It depends on the release into the cytosol of mitochondrial proteins that normally reside in the intramembranous space of mitochondria.
4. A key protein in the intrinsic pathway is cytochrome c, a water soluble component of the mitochondrial electron-transport chain .
5. When released into the cytosol, it binds to an adaptor protein called Apaf1 ( apoptotic protease activating factor-1), causing the Apaf1 to oligomerize into a wheel-like heptamer called an apoptosome.
6. Each Apaf1 contains a caspase recruitment domain (CARD) and these are accumulated at the center hub of the apoptosome.
7. The Apaf1 proteins in the apoptosome recruit initiator caspase-9 proteins, which are thought to be activated by proximity in the apoptosome. This is like the caspase-8 activation in the DISC.
8. The activated caspase-9 molecules then activate downstream executioner caspases to induce apoptosis.

The Intrinsic pathway of apoptosis: Bcl2 protein regulates this apoptosis pathway:

This explanation is well explained in the diagram below. The diagram is informative and appropriate for the exam point-of-view.

The types of Bcl2 family proteins are presented in the diagram below:

This note is made from the Cell Biology Book by Albert.

Other related notes:

1. Cell cycle checkpoints: https://thebiologyislove.com/cell-cycle-checkpoints/
2. Useful numbers for Cell culture: https://thebiologyislove.com/useful-numbers-for-cell-culture/

Facebook link: https://www.facebook.com/share/p/oPmgX6nuJ2CUAqku/?mibextid=oFDknk

Instagram Link: https://www.instagram.com/p/C6yqOp2NDaf/?igsh=OGNzd3dwd2JrZmow