Programmed cell death plays key roles in human health and disease. Signals for cellular life and death are regulated by the BCL-2 family proteins and converge at the mitochondria, where cell fate is ultimately decided. BCL-2 protein activities are critical for maintaining mitochondrial and cellular physiology, and are also linked with major human diseases, especially cancer. Thus, understanding their mechanisms of action has high biomedical priority. The BCL-2 family includes both pro-life (e.g. BCL-XL) and pro-death (e.g. BAX) proteins that exert their regulatory functions through a network of intermolecular interactions as they translocate between the cytoplasm and the mitochondrial outer membrane. Mitochondrial membrane association is a key early step of programmed cell death;however, the exact mechanism through which membrane association mediates BCL-2 protein function is not known. This project focuses on answering the central question: how do the three key BCL-2 relatives, BCL-XL, BAX and BID, transition between soluble and membrane-inserted states to exert their pro- and anti-apoptotic activities?

Public Health Relevance

Mitochondrion-dependent apoptosis is regulated primarily by the BCL-2 family proteins and is linked with major human diseases, especially cancer. Understanding its molecular mechanism of action is directly relevant to human health and is the main goal of this project.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Membrane Biology and Protein Processing (MBPP)
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Knowlton, John R
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Sanford-Burnham Medical Research Institute
La Jolla
United States
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