The Bcl-2 family of proteins regulate and facilitate apoptosis. This family consists of three groups; the pro-survival proteins, the BH3-only proteins and the effector proteins Bax and Bak. In health cells Bax is largely cytosolic. Upon activation by BH3-only proteins, such as Bid and Bim, Bax translocates to the outer mitochondrial membrane and forms large homo-oligomeric complexes. These complexes form pores in the mitochondrial membrane leading to cell death.

BH3 domains interact with Bax by inserting four ‘signature’ hydrophobic residues, (‘h1’ through ‘h4’) into the hydrophobic groove of Bax. In addition to these four hydrophobic residues, the recent Bax:BidBH3 structure (1) has highlighted the importance of two hydrophobic ‘h0’ residues in the BidBH3 peptide (I82/I83) in governing their ability to activate Bax. Like Bid, Bim is a potent activator of Bax and these amino acids in Bim are proline and glutamic acid. To understand the importance of the ‘h0’ position in Bim and how these h0 residues were accommodated, we have determined the structure of BidBH3 in complex with Bax. Comparison with the structure of Bax:BidBH3 allow a dissection of the critical contacts between these two peptides and Bax.

The structure of the pore formed by Bax homo-oligomers is not known and the nature by which Bax engages the mitochondrial membrane to initiate rupture is poorly understood. Data from neutron reflectometry experiments (to be performed in November at ANSTO) will also be presented that investigate how soluble Bax transforms into a membrane embedded entity, providing insights into the effects of Bax permeabilisation on membrane thickness and the type of pore formed by Bax oligomers.