Embedded together: The life and death consequences of interaction of the Bcl-2 family with membranes

Abstract

Permeabilization of the outer mitochondrial membrane is the point of no return in most programmed cell deaths. This critical step is mainly regulated by the various protein-protein and protein-membrane interactions of the Bcl-2 family proteins. The two main models for regulation of mitochondrial outer membrane permeabilization, direct activation and displacement do not account for all of the experimental data and both largely neglect the importance of the membrane. We propose the embedding together model to emphasize the critical importance of Bcl-2 family protein interactions with and within membranes. The embedding together model proposes that both pro-and anti-apoptotic Bcl-2 family proteins engage in similar dynamic interactions that are governed by membrane dependent conformational changes and culminate in either aborted or productive membrane permeabilization depending on the final oligomeric state of pro-apoptotic Bax and/or Bak.

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

“…Ectopic expression of Bcl-2 almost completely blocked apoptosis upon combined treatment with Doxorubicin and PI103 or LY294002 and inhibited loss of mitochondrial membrane potential, cytochrome c release, cleavage of caspase-9, -3, -8 and Bid, as well as translocation of tBid to the mitochondria (Figures 3a-c). Interestingly, Bcl-2 overexpression also prevented Bax conformational change ( Figure 3a, right panel), in line with a recently proposed model that Bax activation is modulated by interactions with and within the mitochondrial outer membrane (Yethon et al, 2003;Leber et al, 2007).…”

BH3-only proteins and their roles in programmed cell death

“…Following that sort of logic, David Andrews recently proposed the 'embedding together' model, which tries to incorporate elements from both the direct and indirect activation model to form a new hypothesis in which the pro-survival proteins promote survival both by inhibiting the BH3-only proteins (direct model) as well as Bax/Bak (indirect model) (Leber et al, 2007). In this model, membrane permeabilization does not occur until Bax/Bak insert multiple sequences into the mitochondrial outer membrane lipid bilayer (Leber et al, 2007;Billen et al, 2008). Bax undergoes a conformational change upon membrane interaction and then a second change triggered by truncated Bid or other activators.…”

Mitochondrial outer membrane permeabilization: a focus on the role of mitochondrial membrane structural organization

“…Unlike other Bcl-2 proteins which are localized in the cytosol in their inactive state, the pro-apoptotic protein Bak is constitutively bound to the membrane protein-voltagedependent anion ion channel (VDAC2) on the MOM in its inactive conformation (Cheng et al 2003;Leber et al 2007). Following the cleavage of Bid to tBid by the activated caspase 8, tBid binds to Bak, displacing VDAC2 to expose its BH3 domain for Bak activation (Cheng et al 2003).…”

“…Upon membrane insertion, the N-terminal fragment is dissociated from the structure to expose the hydrophobic helices (Chou et al 1999) which further promote structural rearrangements that expose the BH3 domain for interaction with Bcl-2 proteins (Oh et al 2005). The active form Bid (tBid) then interacts with inactive Bax via its 6A7 Nterminal epitope resulting in the conformational changes releasing the α9 C-terminus to anchor Bax to the membrane (Leber et al 2007). These specific changes in Bcl-2 protein structure are summarized in Table 2.…”

“…Different BH3-only proteins bind to and neutralize the available pro-survival proteins during apoptosis via different binding affinity of each BH3-only protein (Zong et al 2001). While these two models focus only on regulating the interaction between proteins, the third model, the so-called embedded-together model, proposes the explicit participation of the MOM (Leber et al 2007(Leber et al , 2010Shamas-Din et al 2011). In particular, this model proposes that the mitochondrial membrane induces the conformational changes in the Bcl-2 proteins necessary for pore formation.…”