The intrinsic pathway to apoptosis is governed by the Bcl-2 family of proteins, which respond to cellular stresses such as DNA damage. The proteins within this family share 1 to 4 Bcl-2 Homology domains (BH1 to BH4) and can be divided in three sub-categories according to their function. One subgroup, the BH3-only proteins, is upregulated upon cellular stresses and initiates apoptosis through interactions with other Bcl-2 family members. Another subgroup, the pro-apoptotic Bax or Bak proteins, are the effectors of apoptosis. Upon activation these proteins oligomerize at the mitochondrial outer membrane and provoke its permeabilization. The resulting release of cytochrome c and other pro-apoptotic proteins leads to cell death.
During apoptosis, the BH3-only proteins Bim and Bid can directly activate Bax or Bak by binding to a hydrophobic groove at the surface of Bax or Bak [1-2]. Recently, Iyer et al. discovered that some antibodies can also directly activate Bax or Bak by binding a specific loop (α1-α2) located on the opposite face of the protein to the BH3-only activation site [3]. Crystal structures of Bax monomer bound to a Fab’ fragment derived from one of these antibodies provide the first molecular details of this interaction. The structures reveal that the binding of the antibody induces structural changes within the Bax monomer and thus provide insights into this novel mechanism of Bax activation. This information may aid the development of intrabodies or small molecules aimed at regulating apoptosis.