Unravelling the bcl-2 apoptosis code with a simple model system

Abstract

Using defined lipids and purified proteins, Billen et al. offer a new model to reconcile the two currently opposing models for how Bcl-2 family member interactions regulate cell death.

Figure 1. Schematic Models to Explain the Functional Relationships between Bcl-2 Family Proteins

Depicted are the anti-death Bcl-2-type protein Bcl-XL, the pro-death protein Bax, and the BH3-only proteins Bid (N-terminally truncated Bid or tBid, an activator- or sensor-type), and Bad (sensor-type BH3-only protein). (A) In the sensor-only model, all BH3-only proteins serve to inactivate Bcl-2-like cell death inhibitors, which when released allow activation and oligomerization of Bax. (B) In the split BH3 model, some BH3-only proteins act upstream of Bcl-2-types, while others act downstream. The BH3-only protein tBid is sequestered by Bcl-XL, and when tBid is displaced by sensor-type BH3-only protein Bad, tBid is freed to activate Bax, which in turn oligomerizes in the membrane to facilitate release of pro-apoptotic proteins. (C) In the dual interaction model put forth by Billen and colleagues, Bcl-XL can interact with either Bax or tBid in the same sample.

Figure 2. Putative Conformations of Bcl-XL with a-Helices 2 (BH3 Domain), 5–6 (Central Hairpin), and 9 (C-Terminal Hydrophobic Tail) Depicted in Orange, Green, and Red, Respectively

(A) Structure of Bcl-XL in solution. (B) Membrane-integrated conformation of Bcl-XL in which the C-terminal tail is inserted into the membrane in a transmembrane orientation, while the remainder of the protein maintains the solution structure. In this conformation, the BH3-binding pocket of Bcl-XL is expected to be available to engage in inhibitory groove–BH3 interactions with pro-death Bcl-2 family proteins, such as tBid and Bax, as is seen in solution-based binding studies. (C) Membrane-integrated conformation of Bcl-XL in which the C-terminal tail and the central helical hairpin are inserted into the membrane. In this conformation, the BH3-binding pocket of soluble Bcl-XL is expected to be substantially modified or destroyed. However, Bcl-XL may still engage in neutralizing interactions with Bax, as previously proposed for Bcl-2 [20]. Alternatively, this conformation may correspond to functionally silent Bcl-XL, pro-apoptotic Bcl-XL, or a yet unknown function of Bcl-XL. (D) Membrane-integrated conformation of Bcl-XL, in which many different helical regions of the protein are inserted in the membrane, but with different orientations and at different penetration depths. In this conformation, the BH3-binding pocket of soluble Bcl-XL no longer exists. Nevertheless, it is conceivable that Bcl-XL inhibits pro-apoptotic proteins through interaction surfaces other than the groove and/or via interactions with membrane lipids. Alternatively, this conformation may correspond to functionally silent, pro-apoptotic, or a yet unknown function of Bcl-XL. We postulate that the topology adopted by Bcl-2-type proteins in the membrane can be modulated by changes in membrane lipid composition.