Mcl-1 and Bcl-x sequestration of Bak confers differential resistance to BH3-only proteins.

The prosurvival Bcl-2 family proteins Mcl-1 and Bcl-x inhibit apoptosis by sequestering BH3-only proteins such as Bid and Bim (MODE 1) or the effector proteins Bak and Bax (MODE 2). To better understand the contributions of MODE 1 and MODE 2 in blocking cell death, and thus how to bypass resistance to cell death, we examined prescribed mixtures of Bcl-2 family proteins. In a Bim and Bak mixture, Bcl-x and Mcl-1 each sequestered not only Bim but also Bak as it became activated by Bim.

Dissociation of Bak α1 helix from the core and latch domains is required for apoptosis.

During apoptosis, Bak permeabilizes mitochondria after undergoing major conformational changes, including poorly defined N-terminal changes. Here, we characterize those changes using 11 antibodies that were epitope mapped using peptide arrays and mutagenesis. After Bak activation by Bid, epitopes throughout the α1 helix are exposed indicating complete dissociation of α1 from α2 in the core and from α6-α8 in the latch.