BAX and BAK caught in the act

Abstract

In this issue of Molecular Cell, Kim et al. (2009) describe the steps involved in the direct activation of the proapoptotic proteins BAX and BAK by their BH3-only partners, resolving the controversy regarding direct versus indirect activation of these proteins.

Figure 1. Stepwise Activation of BAX by BH3-Only Proteins

(A) In the cytosolic-inactive state of BAX, the C-terminal hydrophobic helix (α9, red) associates with the canonical BH3-binding groove (red semicircle), and the N-terminal helix α1 (blue) with helix α6 forms the new BH3 interaction site at the polar opposite end of the molecule. (B) The BH3 activator (yellow) associates with the BAX α1/α6 interaction site, triggering a conformational change. (C) This conformational change exposes helices α1 and α9. The BH3 activator remains associated with BAX but now interacts with residues in the BAX BH1 and BH3 domains. (D) The new conformation primes BAX for association with the MOM. (E) BAX oligomerization is driven by the bound BH3 activator. Adapted from Kim et al. (2009).