The protein Bak belongs to a molecular hit squad that spurs apoptosis. Dai et al. reveal that Bak has to make the right connection before it can kill cells.

Bak and its cousin Bax dispatch their victims by perforating the outer membrane of mitochondria, permitting cytochrome c to escape. Researchers think that a family of proteins called BH3-only proteins control this function of Bak and Bax. The leading hypothesis is that some BH3-only proteins, known as direct activators, bind to Bak or Bax and induce them to oligomerize, thereby switching them on. Another group of BH3-only proteins, the sensitizers, latch onto antiapoptotic relatives of Bak and Bax and prevent them from inhibiting activation.

To nail down the details of Bak's activation, Dai et al. followed its interactions with BH3-only proteins in vitro. They found that the protein bound to three direct activators but not to one of the sensitizers. Unlike Bax, which loiters in the cytoplasm until it's needed on the mitochondrion, Bak remains on the mitochondrial membrane. The researchers showed that a lipid milieu wasn't necessary for binding between BH3-only proteins and Bak, although it did strengthen the link between the partners.

The researchers also showed that only a transient interaction between BH3-only proteins and a groove on Bak was required to trigger Bak's oligomerization. Bak couldn't kill cells if the team prevented this brief interaction. Scientists still need to determine the structures of the Bak and Bax oligomers and how they enable the proteins to puncture the mitochondrial membrane.

et al
J. Cell Biol.