Pro-apoptotic cascade activates BID, which oligomerizes BAK or BAX into pores that result in the release of cytochrome c

Abstract

We review data supporting a model in which activated tBID results in an allosteric activation of BAK, inducing its intramembranous oligomerization into a proposed pore for cytochrome c efflux. The BH3 domain of tBID is not required for targeting but remains on the mitochondrial surface where it is required to trigger BAK to release cytochrome c. tBID functions not as a pore-forming protein but as a membrane targeted and concentrated death ligand. tBID induces oligomerization of BAK, and both Bid and Bak knockout mice indicate the importance of this event in the release of cytochrome c. In parallel, the full pro-apoptotic member BAX, which is highly homologous to BAK, rapidly forms pores in liposomes that release intravesicular FITC-cytochrome c *20A Ê . A definable pore progressed from *11A Ê consisting of two BAX molecules to a *22A Ê pore comprised of four BAX molecules, which transported cytochrome c. Thus, an activation cascade of pro-apoptotic proteins from BID to BAK or BAX integrates the pathway from surface death receptors to the irreversible efflux of cytochrome c.

Bak apoptotic pores involve a flexible C-terminal region and juxtaposition of the C-terminal transmembrane domains

“…Linkage at Bak α9:α9 could link BH3:groove dimers to the higher-order oligomers that are associated with pore formation. 26,27 The dimers can also be linked via cysteine residues placed in α6, 18,24,25 and more recently in α3 or α5, 6,21 suggesting a variety of dimer arrangements in the high-order complexes.…”

“…7,[21][22][23] The dimers can be linked via cysteine residues placed in α6, 18,24,25 and more recently via cysteine residues in either α3 or α5, 6,21 allowing detection of the higherorder oligomers associated with pore formation. 26,27 However, whether these interactions are required for high-order oligomers and pore formation remains unclear.Like most Bcl-2 members, Bak and Bax are targeted to the MOM via a hydrophobic C-terminal region. The C terminus targets Bak to the MOM in healthy cells, 28 whereas the Bax C terminus is either exposed 29 or sequestered within the hydrophobic groove until apoptotic signals trigger Bax translocation.…”

“…7,[21][22][23] The dimers can be linked via cysteine residues placed in α6, 18,24,25 and more recently via cysteine residues in either α3 or α5, 6,21 allowing detection of the higherorder oligomers associated with pore formation. 26,27 However, whether these interactions are required for high-order oligomers and pore formation remains unclear.…”

Role of programmed cell death in the immunopathogenesis of sepsis

“…cytochrome c) into the cytosol. Cytosolic cytochrome c binds to Apaf-1, which oligomerizes to assemble the apoptosome that activates procaspase-9 and initiates a downstream caspase cascade resulting in cell death [10][11][12].…”

Divide et impera: Ca2+ signals, mitochondrial fission and sensitization to apoptosis

“…5 Once activated, BH3-only proteins function as ligands for the multidomain proapoptotics BAX and BAK, induce their homo/hetero-oligomerization and ultimately the release of cytochrome c from mitochondria. 6 Several different and sometimes mutually exclusive mechanisms have been proposed to explain the mitochondrial events that lead to the efflux of cytochrome c (see Martinou and Green 7 for a review), often generating more confusion than knowledge.…”