The role of BCL-2 family members in apoptotic cell death

Bcl-2 and related proteins have been shown to play an important role in regulating the susceptibility of cells to undergo apoptosis in response to a wide variety of stimuli. While some members of the Bcl-2 family, including Bcl-2 and BC!-XL, appear to function to prevent programmed cell death, other family members, including Bax and Bak appear to potentiate apoptosis. Although various genetic experiments have confirmed the central importance of Bcl-2 related proteins in regulating cell survival, the exact biochemical functions performed by Bcl-2 proteins remains unclear. In the hopes of gaining further insights into the function of Bcl-2 and related proteins a three-dimensional structure of Bcl-xL has been obtained by both x-ray crystallography and NMR spectroscopy. Mutations introduced into BCI-XL using information derived from the three-dimensional structure has helped define three functionally important domains in the protein. The carboxy terminal domain is necessary and sufficient for targeting the protein to the outer mitochondria! and outer nuclear membranes as well as the endoplasmic reticulum. A large internal domain that is dispensable for antiαpoptotic function was also identified. Nevertheless, this domain plays a regulatory role in the overall function of the protein and appears to be a target for post-translational modifications. The rest of the molecule is organized in a compact o helical bundle, composed of two central hydrophobic a. helices surrounded by amphip 1athic helices. This core structure bears striking similarity to the pore forming domain found in a number of bacteria] toxins. These data suggest the possibility that Bcl-2 and related proteins maintain the homeostasis of key intracellular organelles by regulating membrane permeability. The biochemical and evolutionary implications of these observations will be discussed.