Review
Molecular biology of Bax and Bak activation and action

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Abstract

Bax and Bak are two nuclear-encoded proteins present in higher eukaryotes that are able to pierce the mitochondrial outer membrane to mediate cell death by apoptosis. Thus, organelles recruited by nucleated cells to supply energy can be recruited by Bax and Bak to kill cells. The two proteins lie in wait in healthy cells where they adopt a globular α-helical structure, seemingly as monomers. Following a variety of stress signals, they convert into pore-forming proteins by changing conformation and assembling into oligomeric complexes in the mitochondrial outer membrane. Proteins from the mitochondrial intermembrane space then empty into the cytosol to activate proteases that dismantle the cell. The arrangement of Bax and Bak in membrane-bound complexes, and how the complexes porate the membrane, is far from being understood. However, recent data indicate that they first form symmetric BH3:groove dimers which can be linked via an interface between the α6-helices to form high order oligomers. Here, we review how Bax and Bak change conformation and oligomerize, as well as how oligomers might form a pore. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.

Research Highlights

► During apoptosis, Bax and Bak puncture the mitochondrial outer membrane. ► Bax and Bak activity is regulated by other members of the Bcl-2 family. ► Activation exposes the Bax and Bak BH3 domains to allow oligomerization. ► Bax and Bak oligomers form pores in the outer membrane via unknown mechanisms. ► Structures of oligomeric Bax or Bak may reveal novel drug targets.

Abbreviations

BH
Bcl-2 homology
OM
outer membrane
tBid
truncated Bid
TM
transmembrane

Keywords

Apoptosis
Bak
Bax
Conformation change
Mitochondrion
Mitochondrial permeability
Oligomerization

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This article is part of a Special Issue entitled Mitochondria: the deadly organelle.