Programmed cell death or apoptosis is a genetically programmed physiological process enabling removal of unwanted cells or of cells infected with pathogens. Consequently, apoptosis is essential for the development and maintenance of tissues in multi-cellular organisms. Dysregulation of apoptosis can lead to a wide range of diseases including cancer and neurodegenerative diseases. Elucidation of the signal transduction mechanisms in apoptotic processes at the molecular level could potentially identify therapeutic targets for such diseases.
An important group of molecules known as the BCL-2 (i.e., B-cell lymphoma-2) family of proteins act as critical regulators of the apoptotic pathways involving intracellular organelles such as mitochondria and the endoplasmic reticulum. Certain BCL-2 family members, when activated by cell death signals, are known to undergo conformational changes and insert into the mitochondrial membrane and to form pores, thereby resulting in damage to the integrity of mitochondria, the powerhouse of the cell. Currently, ‘membrane-inserted’ structure is not known for any of the BCL-2 proteins in detail. Furthermore, signal transduction pathways involving certain BCL-2 family proteins are controversial.
Using various biochemical methods and biophysical methods we aim to delineate the mechanism by which the pore-forming BCL-2 proteins become activated by other pro-apoptotic BCL-2 members and how they are organized within the membrane-pore. In particular, using a recently developed biophysical method known as the site-directed spin labeling (SDSL) approach of electron paramagnetic resonance (EPR) spectroscopy we are studying the structure of the BCL-2 proteins in the membrane-inserted state. The detailed structure/function information will provide novel insight that will likely facilitate the identification of drug targets for controlling the apoptotic sequences that occur in many diseases.