Apoptosome - History

History

The term Apoptosome was first introduced in Yoshihide Tsujimoto's 1998 paper "Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria?". However, the Apoptosome was known before this time as a ternary complex. This complex involved caspase-9 and Bcl-XL which each bound a specific Apaf-1 domain. The formation of this complex was then believed to play a regulatory role in mammalian cell death. In December of the same year, a further article was released in The Journal of Biological Chemistry stating that Apaf-1 is the regulator of apoptosis, through activation of procaspase-9.

The criteria for an apoptosome were laid out in 1999. Firstly, it must be a large complex (greater than 1.3 million Daltons). Secondly its formation requires the hydrolysis of a high energy bond of ATP or dATP. And lastly it must activate procaspase-9 in its functional form. The formation of this complex is the point of no return, and apoptosis will occur. The stable APAF-1 and cytochrome mutimeric complex fit this description, and is now called the apoptosome.

The apoptosome was thought to be a mutimeric complex for two reasons. Firstly, to bring multiple procaspase-9 molecules close together for cleavage. And secondly, to raise the threshold for apoptosis, therefore nonspecific leakage of cytochrome c would not result in apoptosis.

Once the apoptosome was established as the procaspase-9 activator, mutations within this pathway became an important research area. Some examples include human leukemia cells, ovarian cancer and viral infections. Current research areas for this pathway will be discussed in further detail. There are hidden routes for cell death as well, which are independent of APAF-1 and therefore the apoptosome. These routes are also independent of caspase-3 and 9. These hidden pathways for apoptosis are slower, but may prove useful with further research.