BCL-2 Family Interactions With 2-Trans-Hexadecenal Define Pro-Apoptotic And Anti-Apoptotic Classifications

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

Cells that become infected or mutated often respond by inducing a suicide program called apoptosis. This program is important to healthy tissues because it ensures that stressed and/or diseased cells are eliminated. Despite the biological importance of apoptosis, the signals that allow for cellular suicide to proceed are incompletely understood. The goal of this project is to understand apoptosis at the single-molecule level using a combination of state-of-the-art techniques that will reveal fundamental biology with applications to biotechnology and medicine. Throughout the duration of this project, research opportunities will be provided to high school students, undergraduate students, post-baccalaureate students, graduate students, and post-doctoral fellows, including those who are underrepresented in science and medicine, with the goal of inspiring and building a diverse scientific workforce. Apoptosis, or programmed cell death, is crucial in biological processes ranging from embryogenesis to carcinogenesis. The BCL-2 (B-cell CLL/Lymphoma 2) family of proteins is a critical regulator in the apoptotic pathway with both pro-apoptotic and anti-apoptotic functions, making it crucial to understand its underlying mechanisms. BCL-2 proteins such as BAX (BCL-2 associated X protein, the major pro-apoptotic BCL-2 protein), collaborate with other BCL-2 family proteins, leading to the creation of proteolipid pores in the outer mitochondrial membrane (OMM). This causes the OMM to become permeable, allowing pro-apoptotic proteins to leak out of the mitochondria to activate caspases and cell apoptosis. While nearly three decades of literature suggest protein-protein interactions within the BCL-2 family delineates anti-apoptotic from pro-apoptotic function, new preliminary data reveal that lipid binding into an uncharacterized hydrophobic pocket in pro-apoptotic members is the true determinant of pro-apoptotic function. The scientific aims of this project are to reveal a detailed structure-based mechanism of how mitochondrial lipids directly alter the conformation of BAX to result in its activation and to expand upon these transformative concepts by engineering lipid-binding domains into anti-apoptotic BCL-2 proteins to evaluate their molecular and cellular functions. In parallel, a major overarching goal of this project is to nurture, inspire, and advance the career development of young scientists at all levels by preparing a diverse biomedical research workforce armed with the methodological skills, analytical acumen, and scientific knowledge. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.