Antagonistic Gaussian Membrane Curvatures: A New Perspective in BCL-2 Family Regulation of Apoptosis

Apoptosis, also known as programmed cell death, is essential for maintaining cellular homeostasis and development. Disruptions or impairments in apoptosis can contribute to a range of diseases, including cancer and neurodegenerative diseases. The BCL-2 family of proteins plays a pivotal role in the regulation of apoptosis by controlling the permeabilization of the mitochondrial outer membrane (MOM). These proteins act as key integrators of various cellular stress signals to govern the activation of the intrinsic apoptotic pathway. The pro-apoptotic effector BAX relocates to the MOM, where it undergoes conformational changes and triggers the release of cytochrome c and other factors into the cytosol, ultimately committing the cell to apoptosis. The anti-apoptotic BCL-XL protein suppresses apoptosis by inhibiting MOM permeabilization and is crucial in driving oncogenic transformation. The regulation of the BCL-2 family has conventionally been based on interactions involving the BH3 domain. Despite recent insights, direct binding evidence remains incomplete, and experiments have shown that BCL-XL exhibits activity independent of BH3 domain binding. Thus, a comprehensive understanding of how BCL-XL inhibits BAX-induced pores remains unresolved, particularly given the high structural similarity between BAX and BCL-XL. Leveraging a novel artificial intelligence framework, calibrated using X-ray structural data, we demonstrate that BAX and BCL-XL generate antagonistic Gaussian membrane curvatures, offering an additional mechanism for regulating transmembrane pore formation and closure. This is in agreement with our in vitro observations that membrane permeabilization inhibition is not specific to BCL-2 family proteins, as other curvature-generating motifs can similarly suppress BAX activity. These findings suggest that, beyond direct protein-protein interactions, BCL-2 family proteins induce opposing Gaussian membrane curvatures and can interact with one another via a membrane-curvature mediated mechanism. The universal aspect of curvature-mediated interactions provides complementary regulation to specific binding, implying that mitochondrial membranes could play a key role in BCL-2 family dynamics.