Apoptosis subsequently formed when two heterodimers join (Figure 1a).

Apoptosis is a highly controlled cell suiciding process. It is often referred as programmed cell death. Apoptosis occurs in both animals and plants. It has a significant role in the development of multicellular organisms and processes such as cell turnover and functioning of the immune system. The cells that undergo apoptosis have some morphological changes: shrinking, condensing, collapsed cytoskeleton, breakdown of nuclear envelope and chromatin condensation. Larger cells usually turn into apoptotic bodies. The chemical characteristics of the cell membrane are also changed so that a macrophage would engulf the cells.Apoptosis is mediated by caspases (Cysteine-Aspartic proteases). Caspases have specific cysteine protease activity; cysteine at their active site cleaves their target protein at specific aspartic acids. Caspases are made in cells as procaspases, which are inactive forms of caspases. They are activated by proteolytic cleavage, where it happens at one or two specific aspartic acids, and the active caspases catalyse the process. In the reaction, the procaspase is divided into a small and a bigger subunit that forms a heterodimer (two different proteins). An active tetramer is subsequently formed when two heterodimers join (Figure 1a). The newly formed active caspase (initiator procaspase) can then activate the other procaspases (executioner procaspases); this causes an amplifying chain reaction, hence a proteolytic caspase cascade (Figure 1b). The executioner caspases cleave the target proteins and the nuclear lamins (Figure 1b). The cleavage of the protein that holds an endonuclease enables the enzyme to cut up the DNA in the nucleus. The cleavage of the other proteins such as those involved in the cytoskeleton and cell-cell adhesion proteinsFigure 1a – Procaspase activationFigure 1b – Caspase cascadeLAM 2causes the cell to change shape and separate from its neighbouring cells. Therefore, the cell can be engulfed more easily by the neighboring cell. There are two most well-studied activation mechanisms for the initiation of apoptosis: the intrinsic pathway (mitochondrial pathway) and the extrinsic pathway (death receptor pathway). Although there is evidence suggests that the two pathways are interconnected which the molecules in one pathway can affect the other (Igney and Krammer, 2002).The extrinsic pathway involves death receptors on the cell surface. Death receptors are transmembrane proteins that transmit apoptotic signals initiated by specific ligands. They belong to the family of tumor necrosis factor (TNF) receptors and the Fas receptor. Figure 2 shows the extrinsic pathway of apoptosis activated through Fad death receptors: Fas ligand on the surface of a cytotoxic lymphocyte activates Fas death receptors on the target cell. The cytosolic tail of Fas subsequently recuits the adaptor protein FADD (Fas-associated death domain) by the death domain on each protein. The FADD protein then recruits an initiator procaspase, which can be procaspase-8, procaspase-10, or both, by a death effector domain on both FADD and the procaspase. This creates a death-inducing signaling complex (DISC). The initiator procaspase molecules in the DISC are activated as they are packed closely. TheFigure 2 – The extrinsic pathway of apoptosis activated through Fad death receptorsLAM 3activated protease is stabilised into a caspase as the activated procaspases cleave one another. Apoptosis occurs as a caspase cascade is produced, which is caused by the cleavage and activation of the executioner procaspases by caspase-8 and caspase- 10. The extrinsic pathway can be inhibited extracellularly or intracellularly by the cell using inhibitory proteins. One example is the decoy receptor which inhibits the death receptors competitively as it has a ligand binding domain but not a death domain. Hence, there is binding to a death ligand but yet apoptosis is not activated.Intrinsic apoptosis is mitochondrial-mediated. Proteins that usually stay inside of the intermembrane space of mitochondria are released into the cytosol. Some of the released proteins may activate apoptosis by activating caspases proteolytic cascade. A protein called cytochrome c, which is part of the mitochondrial electron transport chain, is released in the intrinsic pathway. In the cytosol, cytochrome c binds to Apaf1 (apoptotic protease activating factor 1), which is a procaspase-activating adaptor protein. This causes the Apaf1 protein to form an oligomer called apoptosome, which is a heptamer. Afterwards, the Apaf1 proteins bring in the initiator procaspase proteins (procaspase-9) and they become activated. The activated caspases then activate the executioner procaspases, causing apoptosis.Regulation of the amount of apoptosis is important. Either too much or too little apoptosis can cause diseases. When there are too many cells carrying out apoptosis, tissue damage occurs. Too little apoptosis may lead to cancer or autoimmune diseases as the number of cells does not decrease and the lifespan of the cells increases, which causes accumulation of cells. The intrinsic pathway of apoptosis can be regulated by the BCL-2 family of proteins. They control the release of the intermembrane mitochondrial proteins including cytochrome c into the cytosol. These proteins can be pro-apoptotic and anti-apoptotic; the former encourages apoptosis by promoting the release of proteins and the latter reduces apoptosis by inhibiting the release hence activation of caspase proteases (Newmeyer et al., 2000). Those two proteins can inhibit each other by forming heterodimers. Whether the cell dies or not is largely determined by the level of each type of activity. One way of regulating intrinsic pathway of apoptosis is shown in Figure 3. In this example, Bcl2 and Bcl-XL are involved, which are anti-apoptotic proteins. The pro-apoptotic Bcl2 proteins have two subtypes – the BH123 proteins and the BH3-only proteins. Figure 3 shows that when there aren’t any apoptotic stimuli, the BH123 proteins on the outer membrane of the mitochondria are inhibited by the anti-apoptotic Bcl2 proteins. When there is an apoptotic stimulus, the BH3-only proteins are activated and bind to the anti-apoptotic Bcl2 proteins. As a result, the anti-apoptotic Bcl2 proteins can no longer inhibit the BH123 proteins. ThisLAM 4causes activation and aggregation of the BH123 proteins on the outer membrane, promoting the release of intermembrane proteins into the cytosol.Figure 3 – Regulation of intrinsic pathway of apoptosis (pro-apoptotic BH3-only and anti-apoptotic Bcl2 proteins)Programmed cell death can be initiated via the intrinsic and extrinsic pathway; both eventually lead to the activation of executioner procaspases. Some evidence suggests that those pathways are linked and the molecules of one pathway can influence the other (Igney and Krammer, 2002). Although we know that the intrinsic pathway relies on the release of intermembrane mitochondrial proteins such as cytochrome c, the mechanism of how the proteins are released is still unknown.

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