Matters of Life and Death: Give and Take in the Bcl-2 Family

The mitochondrial pathway of apoptosis, a major mode of cell death in vertebrate animals, is characterized by the process of mitochondrial outer membrane permeabilization (MOMP), in which proteins of the mitochondrial inter-membrane space gain access to the cytosol, thereby triggering caspases and apoptosis. This life-or-death decision is controlled by the proteins of the Bcl-2 family. These include the pro-apoptotic Bcl-2 effector proteins, Bax and Bak, that cause the permeabilization event, and the anti-apoptotic proteins, e.g., Bcl-2, Bcl-xL, Mcl-1, which prevent it. A third sub-family, the BH3-only proteins, which include Bid, Bim, Bad, Puma, and Noxa (among others), regulate the other two sub-families, promoting the activation of the effectors or blocking the activity of the anti-apoptotic proteins (or both). Structural studies have led to a greater understanding of these complex interactions and have provided the basis for the development of BH3-mimetics that show promise for cancer therapies. New structural studies have begun to elucidate the mechanisms whereby Bax and Bak become activated, opening new avenues towards promoting or inhibiting the mitochondrial pathway of apoptosis. A proposed “hit and run” model of effector activation, whereby a BH3-only protein engages Bak or Bax and then must be displaced as the effector proteins associate, was validated in these structural studies. Additional, emerging insights will be discussed in the context of a unified model of Bcl-2 protein interactions.