Role of the Mitochondrial Membrane in Apoptosis

The Bcl-2 family of proteins is crucial for apoptosis (a form of programmed cell death) regulation. The Bcl-2 proteins are synthesized in cytosolic ribosomes before reaching the lipid bilayer, where they insert through a specific C-terminal anchoring transmembrane domain. The members of this family of proteins target the mitochondrial outer membrane where they hierarchically interact to determine cell fate. There is now significant structural information on both anti-apoptotic and pro-apoptotic Bcl-2 family proteins, how they interact with their ligands and more recently, the types of conformational changes they undergo. Whilst protein-protein interactions between the functionally opposing factions of the Bcl-2 protein family ultimately regulate the apoptotic program, there is growing evidence that interactions between these proteins and the lipids of the mitochondrial (and probably endoplasmic reticulum) membranes also play a critical role in their functioning. These interactions, however, still remain poorly understood. Due to the recognised importance of the role of membranes in the function of Bcl-2 family members this project aims to characterise the membrane binding properties of these proteins will inform the mechanism of Bcl-2 family mediated apoptosis. The overall aim of this proposal therefore is to perform a systematic evaluation of the membrane interactions of the Bcl-2 family of proteins in complementary biophysical and cellular. This project will therefore redefine our understanding of the mechanism of apoptosis and provide new avenues for the development of compounds to selectively modulate diseases in which apoptosis is dysregulated.