The Bcl2 Family Proteins and Programmed Cell Death

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Programmed cell death is initiated when death signals activate the caspases, a family of otherwise dormant cysteine proteases. External stress stimuli trigger the ligation of cell surface death receptors, thereby activating the upstream initiator caspases, which in turn process and activate the downstream cell death executioner caspases (Denault and Salvesen 2002). In addition, caspases can be activated when stress or developmental cues within the cell induce the release of cytotoxic proteins from mitochondria. This intrinsic mitochondrial pathway for cell death is regulated by the relative ratios of the pro- and anti-apoptotic members of the Bcl-2 protein family.

Several Bcl-2 family members have been identified in humans, including both anti-apoptotic (cytoprotective) and pro-apoptotic (death-promoting) proteins (Green and Reed 1998; Kroemer and Reed 2000; Cory and Adams 2002; Danial and Korsmeyer 2004). The relative ratios of the pro- and anti-apoptotic proteins determine the ultimate sensitivity and resistance of cells to diverse death-inducing stimuli, including chemotherapeutic drugs, radiation, growth factor deprivation, loss of cell attachment to extracellular matrix, hypoxia, infection, and lysis by cytolytic T cells. Imbalances in their relative expression levels and activities are associated with major human diseases, characterized by either insufficient (cancer, autoimmunity) or excessive (AIDS, Alzheimer's disease) cell death.

The Bcl-2 proteins span approximately 200 amino acids, and share sequence homology in four evolutionarily conserved domains (BH1-BH4), of which the BH3 domain is highly conserved and essential for both cell killing and oligomeri-zation among Bcl-2 family members (Fig. 2.1). The anti-apoptotic family members have all four domains, while all of the pro-apoptotic members lack BH4, and some others only have BH3. These BH3-only proteins are activated by upstream death signals, which trigger their transcriptional induction or post-translational modification, providing a key link between the extrinsic death receptor and intrinsic mitochondrial pathways to cell death. Most family members also have a hydrophobic C-terminus (C) which is sufficiently long to span the membrane, and is essential for membrane targeting.

The apoptosis regulatory activities of the Bcl-2 family proteins are exerted through binding with other Bcl-2 family members, binding with other non-ho-

Fig. 2.1. Domain organization (a) and amino acid sequences (b) of human Bcl-XL and Bid. The helices (HI to H8) are those Identified in the solution NMR structures of Bcl-XL (Muchmore et al. 1996; Aritomi et al. 1997) and Bid (Chou et al. 1999; McDonnell et al. 1999) shown in (c).The central core helices are H5 and H6 In Bcl-XL and H6 and H7 In Bid. The C-termlnal hydrophobic segment of Bcl-XL Is denoted as C.The putative lipid binding motif of Bid is denoted as LB. The sequence oftBId starts at Gly61,and the arrow marks the caspase-8 cleavage site at Asp60

mologous proteins, and through the modulation of ion-conducting pores that are thought to influence cell fate by regulating mitochondrial physiology. Their functions are also regulated by subcellular location, as the proteins cycle between soluble and membrane-bound forms. For example, some family members, like anti-apoptotic Bcl-XL, localize to mitochondrial, endoplasmic reticulum, or nuclear membranes, while others, like pro-apoptotic Bid, are found in the cytosol, but are stimulated by death signals to target the mitochondrial outer membrane, where they participate in cytochrome-c release and apoptosis.

The structures of Bcl-XL and Bid, in solution, are very similar. They consist of seven (Bcl-XL) or eight (Bid) a-helices arranged with two central somewhat more hydrophobic helices which form the core of the molecule (Fig. 2.1). In Bcl-XL, the third helix spans the BH3 domain, and is connected to the first helix by a long flexible loop, while helices 5 and 6 form the central hydrophobic hairpin (Muchmore et al. 1996; Aritomi et al. 1997). The structure was determined for a truncated form of the protein lacking the hydrophobic C-terminus. In Bid, the third helix contains the BH3 domain and is connected to the first two helices by a long flexible loop, which includes Asp60, the caspase-8 cleavage site. The hydrophobic hairpin is formed by helices 6 and 7 (Chou et al. 1999; McDonnell et al. 1999). Despite the lack of sequence homology, the structures of Bcl-XL and Bid are strikingly similar to each other, and those of other pro- and anti-apoptotic Bcl-2 family proteins (Suzuki et al. 2000; Petros et al. 2001; Huang et al. 2002; Denisov et al. 2003; Hinds et al. 2003; Huang et al. 2003; Day et al. 2004; Day et al. 2005). Interestingly, they are also similar to the structure of the pore-forming domains ofbacterial toxins, and, like the toxins and other Bcl-2 family members, they also form ion-conducting pores in lipid bilayers (Cramer et al. 1995; Schen-del et al. 1998; Schendel et al. 1999).

The structural basis for Bcl-2 pore formation is not known, since the structures that have been determined are for the soluble forms of the proteins, and pore formation by the Bcl-2 family proteins has not been established in vivo. Nevertheless, by analogy to the bacterial toxins, the Bcl-2 pores are thought to form by a rearrangement of their compactly folded helices upon contact with the mitochondrial membrane. One model proposes membrane insertion of the core helical hairpin with the other helices folding up to rest on the membrane surface, while an alternative model envisions the helices rearranging to bind the membrane surface without insertion. A third possible mechanism for the regulation of mitochondrial physiology by the Bcl-2 proteins is through their interaction with other mitochondrial channels.

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