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Apoptosis – – a highly regulated process

Apoptosis, also known as programmed cell death, is an important normal process that has been occurring in your body for many years – even before you were born. At an early stage of fetal development, your fingers were "webbed", much like an adult frog's. But as a human, a developmental program kicked in that triggered the resorption (death) of the cells that made up these flaps of skin between your fetal fingers. As another example, your brain initially developed with many more neuronal cells than you need to be a functioning human. And so, a tightly regulated program of cell death (apoptosis) occurred during your fetal development to prune back your neural network – leaving you with just the right density of neurons, which you are now busy training, as you learn about – – – apoptosis. Kind of spooky. . .

Because apoptosis results in the efficient destruction of cells, it is very important that this pathway is regulated so that cell death occurs only under specific circumstances. To that end, take a look at the figure below. This figure represents just a subset of the proteins involved in the regulation of apoptosis. Do NOT memorize this figure for the Protein Modeling event. This figure is just intended to illustrate the complexity of this pathway. For the Protein Modeling event, we are narrowing our focus to just a few of these proteins – – XIAP, Smac/Diablo, Caspase–3 and PARP.

Apoptosis pathway

 

Caspase – – the executioner.

The "executioner" of the apoptosis pathway is a family of proteins called "caspases". The name "caspase" gives clues as to what the protein does. These proteins are cysteine proteases, which means that these proteins use a cysteine residue in the active site of the enzyme to cleave target proteins (enzymes that cleave proteins are called proteases). Caspases cleave target proteins in specific sites, keying in on a specific reside – aspartic acid. When caspase is active, this enzyme cuts proteins at a peptide bond following an aspartic acid.

Caspases are synthesized initially in a proenzyme form, called zymogen, which means that this protein is initially unable to cleave target proteins. Caspase zymogens undergo proteolytic cleavage themselves to become active. If you look closely at the caspase protein, you will see that the functional protein is actually comprised of two monomers, each of which is comprised of two chains. These two chains were originally a single chain, and during the activation process, this chain was cleaved to generate two chains.

A cell cannot have caspases active all of the time, as this would lead to death of all cells. As part of the intricate pathway of regulating apoptosis, there are proteins that bind to caspases to prevent their activity within the cell. XIAP is an inhibitor of apoptosis protein that binds to, and inhibits, caspase–3. When XIAP is bound to caspase–3, the protease is not active. It is poised, ready to be active is XIAP is removed. In this way, the cell can quickly respond to signals to initiate the apoptotic pathway.

Smac/Diablo and PARP

When a cell activates the apoptotic pathway, one of the proteins involved in the activation process is the Smac/Diablo protein. Smac/Diablo is released from the mitochondria upon activation of the apoptotic pathway. This protein binds to XIAP, thus alleviating the inhibitory action of XIAP on caspase–3, allowing the full activation of the protease, setting the cell on a course of destruction.

Once active, caspase–3 can cleave several target proteins, one of which is PARP. PARP is involved in repairing DNA damage. If PARP is cleaved, it is no longer active and DNA cannot be repaired. The destruction of DNA within the nucleus is a hallmark feature of apoptosis.

 

The Proteins of Apoptosis...

The structures of the various proteins involved in the regulation of apoptosis are shown below – – as interactive Jmol images.

XIAP in a Normal and Healty Cell:

 

XIAP in a Cell Undergoing Apoptosis: