Genetics of Apoptosis

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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.
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