Apoptosome

Apoptosome is a large quaternary protein structure which plays a critical role in the process of apoptosis, or programmed cell death. It is formed in the intrinsic pathway of apoptosis upon the release of cytochrome c from the mitochondria into the cytosol of a cell. The apoptosome acts as a platform for the activation of initiator caspases, particularly caspase-9, which then go on to activate effector caspases leading to the execution phase of apoptosis.

Formation

The formation of the apoptosome is initiated when cytochrome c is released from the mitochondria into the cytosol. This release can be triggered by various stress signals, including DNA damage, oxidative stress, and withdrawal of growth factors. Once in the cytosol, cytochrome c binds to Apaf-1 (apoptotic protease activating factor 1) in the presence of dATP or ATP, leading to the oligomerization of Apaf-1 into a heptameric structure. This heptamer forms the core of the apoptosome.

Structure

The apoptosome is composed of seven Apaf-1 molecules, which come together to form a wheel-like structure. Each Apaf-1 molecule in the apoptosome can bind one molecule of cytochrome c, facilitating the recruitment and activation of procaspase-9. The binding of procaspase-9 to the apoptosome is mediated by the interaction between the CARD (caspase recruitment domain) of procaspase-9 and the CARD of Apaf-1. This interaction is crucial for the activation of caspase-9, which then cleaves and activates downstream effector caspases, such as caspase-3 and caspase-7, leading to the execution phase of apoptosis.

Function

The primary function of the apoptosome is to serve as a platform for the activation of caspase-9, an initiator caspase in the intrinsic pathway of apoptosis. The activation of caspase-9 subsequently leads to the activation of effector caspases, which execute the apoptotic program by cleaving various cellular substrates. This process results in the characteristic morphological and biochemical changes associated with apoptosis, including cell shrinkage, chromatin condensation, DNA fragmentation, and the formation of apoptotic bodies.

Clinical Significance

The apoptosome plays a crucial role in maintaining cellular homeostasis and preventing the development of diseases. Dysregulation of apoptosome formation or function can lead to a variety of diseases, including cancer, autoimmune diseases, and neurodegenerative disorders. In cancer, for example, mutations that impair the formation or function of the apoptosome can prevent the apoptosis of damaged or transformed cells, contributing to tumor development and progression. Conversely, excessive activation of the apoptosome can lead to excessive cell death, as observed in certain neurodegenerative diseases.