This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.During apoptosis, mitochondria release intermembrane proteins to the cytoplasm to activate caspases and this step is critical. The Bcl-2 family proteins regulate the permeability of mitochondrial outer membrane, however, the molecular mechanisms of permeabilization is unclear. Visualization of lipid bilayer will aid our understanding of how Bcl-2 family proteins interact with the membrane.Apoptosis pathways are defective in most cancers and reactivation of them would be most logical in treatment. Most cells do not survive and prolifrerate after mitochondria are permeabilized, therefore, understanding of molecular mechanisms of mitochondrial outer membrane permeabilization is important for therapeutic intervention. We have developed in vitro vesicle systems (outer membrane vesicles and liposomes) to recapitulate membrane permeabilization by Bcl-2 family proteins, then tried to visualize the vesicles when permeabilization occurred. Conventional TEM didn't reveal any membrane changes in the outer membrane vesicles, suggesting the changes are subtle and transient. Cryo-EM is suited to capture transient changes, and could also be used to visualize molecules in the membrane.
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