Genetics of Apoptosis

Figure 5. Model for the function of the multidomain proteins.

In normal cells, inactive monomeric Bax (rectangle) is present in the cytosol. When

cells are exposed to apoptotic stress stimuli, upstream signaling cascades are

136 GENETICS OF APOPTOSIS

activated, here exemplified by Bid. Bid is proteolytically processed into tcBid, which

interacts with Bax and induces conformational changes in Bax (oval). Whether this

takes place in the cytosol or at the mitochondrial membrane is unclear. The

conformational changes trigger Bax oligomerization and insertion into the outer

mitochondrial membrane. Bax forms high-conductance channels through which

cytochrome c (black oval) and other proteins from the intermembrane space are

released into the cytosol. In the cytosol, cytochrome c forms a complex with Apaf-1,

dATP, and procaspase-9. Upon complex formation, caspase-9 is activated.

Caspase-9 subsequently activates executioner caspases, such as caspase-3, triggering

a pathway ultimately leading to apoptotic cell death.