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New Study Findings about Pro-apoptotic Protein Bax

On June 8, EMBO JOURNAL published online a collaborative research paper, “An amphipathic Bax core dimer forms part of the apoptotic pore wall in the mitochondrial membrane”, by Ouyang Bo’s team from the Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences, Lin Jialing’s team from Oklahoma University Health Science Center in the United States, and David W. Andrews’ team from Sunnybrook Research Institute in Canada. In this study, the precise three-dimensional structure of the core domain of the pro-apoptotic protein Bax on lipid bilayer membranes was solved by nuclear magnetic resonance technology, and the key function of this structure in the pore-forming process of Bax in mitochondrial membranes was demonstrated by structure-guided gene mutation and in vitro activity studies. The study advances the understanding of the molecular mechanisms by which proteins form pores in membranes.

 

Apoptosis is an important means to maintain the dynamic balance of cell numbers, and abnormal apoptosis will lead to the occurrence of many diseases. Bax is a key pro-apoptotic protein, which plays an indispensable role in regulating the mitochondrial apoptotic pathway. Under normal circumstances, Bax resides in the cell matrix as a monomer. When the cell receives the apoptosis signal, Bax will be activated and form multimeric holes in the mitochondrial membrane, releasing cytochrome C, thereby starting the apoptosis program. The Bax monomer is a globular protein composed of nine α helices, which will release the hydrophobic α9 helix and bind to the mitochondrial membrane after activation. However, what is the state of Bax on the membrane, and how to form holes to change mitochondrial permeability and promote cell apoptosis, has not been answered for a long time.

 

Ouyang Bo’s team analyzed the precise three-dimensional structure of Bax’s core domain α2-α5 complex in the lipid bilayer membrane system for the first time through nuclear magnetic resonance technology, and found that α4 and α5 formed a flat hydrophobic plane. Using protein-phospholipid NOE and paramagnetic probe titration method, the precise position of Bax (α2-α5) on the membrane was further determined, and it was found that the hydrophobic plane sides of Bax (α2-α5) α4 and α5 were attached to the edge of the membrane. It forms an angle of 60o with the membrane to maximize the protection of the hydrophobic phospholipid bilayer. Among them, R89, F93, F114, A117 and S118 are the key amino acids that interact with the membrane.

 

Based on this NMR structure, Lin Jialing’s team prepared R89E, F93E, F114E, A117D, and S118D mutations to disrupt the electrostatic or hydrophobic interaction between Bax and the membrane, and used liposome fluorescent pigment release experiments to test whether Bax can still form holes, and the results showed that these mutants significantly reduced Bax’s membrane-breaking activity; The David W. Andrews team further performed mitochondrial membrane permeability experiments in cells and also confirmed that these mutants had decreased pore-forming ability in native mitochondrial membranes. These structural and functional experiments reveal the unique pore-forming pattern of the apoptosis protein Bax on the mitochondrial membrane and expand the understanding of the pore-forming mechanism on the pore-forming protein membrane.

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