What are the important conformation changes in Bak and Bax that allow pore formation in mitochondria
To define the major structural changes in Bak and Bax that occur during apoptotic pore formation, we are using a range of biochemical and structure-based approaches. We recently reported that a crucial initial step in Bak-mediated apoptosis involves exposure of the BH3 domain, which then binds to the hydrophobic groove of a second Bak molecule to form symmetric dimers. How dimers then interact to form the large complexes thought necessary to form a pore in the mitochondrial outer membrane is being investigated. Conformation changes in other regions of Bak and Bax are also being analysed by several techniques including exposure of antibody epitopes and cross-linking of cysteine residues placed at specific positions in the Bak protein. To complement our biochemical studies, we are collaborating with the Structural Biology Division to obtain structures of activated Bak and Bax.
These studies aim to identify each step in the formation of mitochondrial pores by Bak and Bax, the point of no return in apoptotic cell death. Each step is a potential target for therapeutic intervention in certain cancers and degenerative diseases.