Bcl-2 Oligomerizes Bax on the Mitochondrial Membrane Surface Preventing the Initial Stages of Apoptosis

Abstract for the article:

The Bcl-2 family of proteins tightly controls mitochondrial outer membrane (MOM) pore formation, crucial to cellular clearance via apoptosis. However, the molecular principles by which opposing family members inhibit, mediate or promote MOM perforation remain elusive. Here, we show structurally that cell-protecting Bcl-2 directly sequesters cell-killing Bax into a protein-protein complex at the membrane interface to prevent Bax forming apoptotic pores. Neutron reflectometry provided a molecular picture of the underlying mechanism. Bax association with Bcl-2 occurs through the formation of Bax protein oligomers on the membrane surface. Bax association with the membrane surface was proportional to the membrane-embedded Bcl-2 levels suggestive of protein-protein complex formation through both Bcl-2/Bax and Bax/Bax interactions. This Bcl-2/Bax sequestration to prevent perforation was observed in membrane models with and without pro-apoptotic cardiolipin present. Our findings shed fundamental new light on the communication of Bcl-2 with its cell-killing relatives at the mitochondria´s membraneous exterior to prevent cells from undergoing apoptosis. 

Here:

The Neutron Reflectometry data and data analysis scripts for Rascal software, attenuated total reflection infrared (ATR-IR) data and AlphaFold simulations.