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?
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.
|Fabre, Lucien; Santelli, Eugenio; Mountassif, Driss et al. (2016) Structure of anthrax lethal toxin prepore complex suggests a pathway for efficient cell entry. J Gen Physiol 148:313-24|
|Kuwana, Tomomi; Olson, Norman H; Kiosses, William B et al. (2016) Pro-apoptotic Bax molecules densely populate the edges of membrane pores. Sci Rep 6:27299|
|Yao, Yong; Nisan, Danielle; Fujimoto, Lynn M et al. (2016) Characterization of the membrane-inserted C-terminus of cytoprotective BCL-XL. Protein Expr Purif 122:56-63|
|Xu, Xiao-Ping; Kim, Eldar; Swift, Mark et al. (2016) Three-Dimensional Structures of Full-Length, Membrane-Embedded Human Î±(IIb)Î²(3) Integrin Complexes. Biophys J 110:798-809|
|Godoi, Paulo H C; Wilkie-Grantham, Rachel P; Hishiki, Asami et al. (2016) Orphan Nuclear Receptor NR4A1 Binds a Novel Protein Interaction Site on Anti-apoptotic B Cell Lymphoma Gene 2 Family Proteins. J Biol Chem 291:14072-84|
|Xu, Xiao-Ping; Volkmann, Niels (2015) Validation methods for low-resolution fitting of atomic structures to electron microscopy data. Arch Biochem Biophys 581:49-53|
|Yao, Yong; Fujimoto, Lynn M; Hirshman, Nathan et al. (2015) Conformation of BCL-XL upon Membrane Integration. J Mol Biol 427:2262-70|
|Volkmann, Niels; MartÃ¡sek, Pavel; Roman, Linda J et al. (2014) Holoenzyme structures of endothelial nitric oxide synthase - an allosteric role for calmodulin in pivoting the FMN domain for electron transfer. J Struct Biol 188:46-54|