Apoptosis is an essential process in multicellular organisms of altruistic cell suicide that is critical for development and the maintenance of homeostasis. From the simple flatworm C. elegans to higher organisms including humans, there exists an evolutionarily conserved group of proteins that regulate the intrinsic apoptotic pathway known as the Bcl-2 protein family. Mitochondrial outer membrane permeabilisation (MOMP) by Bcl-2 family effector proteins Bak and Bax is the pivotal step in the intrinsic pathway that releases apoptogenic factors from the intermembrane space, resulting in the activation of caspases and subsequently the morphological changes characteristic of apoptotic cell death.
The events preceding MOMP, including activation of Bak and Bax by BH3-only proteins followed by formation of symmetric homodimers, have been well characterised by structural and biochemical studies. What is currently lacking is a clear picture of how these homodimers interact with the membrane and self-associate into large membrane-permeabilising oligomers. We have solved several structures of the dimerisation or "core" domain of Bak in complex with detergents and lipids, to our knowledge the first case of such complexes involving a Bcl-2 protein. The structures have implications for Bak oligomerisation, as well as membrane destabilisation and pore formation by Bak oligomers.