施一公,凋亡蛋白 z-bio 2025-07-05 3517

　　In 1997, when Professor Shi Yigong established an independent laboratory at Princeton University, he turned his attention to the field of apoptosis research. Among them, BAX protein, as the key executor of endogenous apoptosis, can accurately drill holes in the outer membrane of mitochondria to release pro-apoptotic factors and trigger cell death, have always been an unsolved mystery in the academic community.

　　The solution to this puzzle is inseparable from a long march of scientific research that spans decades. From Princeton's laboratory to Tsinghua University's podium, and then to the innovative hotbed of West Lake University, Professor Shi Yigong has led generations of scientific researchers to continue to work hard.

　　Finally, on June 27, 2025, Shi Yigong's team published a research paper entitled "Structural basis of BAX pore formation" in Science, analyzing the basic repeat unit structure shared by BAX linear/cyclic polymers, and answering how "Death" BAX has brought cells to the path of death's fate.

　　"Death" BAX is here

　　The BCL-2 protein family is an important regulator of mitochondria-mediated apoptosis, which determines whether the cells will survive or die.

　　Among them, "Death" BAX is a "proapoptotic" protein.

　　Under normal circumstances, BAX lives in the cytoplasm and is on standby. Once cells encounter problems such as growth factor depletion, aging, or DNA damage during growth, BAX will be activated.

　　After activation, the BAX has a clear goal and will run to the mitochondrial outer membrane of the "energy factory" as soon as possible. They are not fighting alone, but a group of BAX teamed up to form linear, arc, and ring... Although the formations are different, they have a common task: "punch holes" on the outer membrane of mitochondria to destroy the stability of the membrane.

　　Ketelut-Carneiro, N., & Fitzgerald, K. A. (2022). Journal of molecular biology, 434(4), 167378.

　　The holes drilled by BAX are not regular protein channels, but "wounds" of various shapes and sizes. Over time, as more and more BAX is activated, these "wounds" will become bigger and bigger.

　　This hole punching process is called "increased permeability of mitochondrial outer membrane".

　　Once it occurs widely, it will cause some "proapoptotic factors" that were originally "sealed" in the mitochondria to escape to the cytoplasm, such as cytochrome c and SMAC. Cytochrome C is responsible for activating the protease caspase, which is closely related to cell apoptosis. SMAC is responsible for relieving the inhibition of caspase by other proteins, pulling and pushing, allowing cells to go on a path of no return.

　　The true face of "Death" BAX

　　As early as 1993, BAX was identified as a "proapoptotic" protein.

　　As a kind of perforated protein, BAX is very different from some similar ones. It does not need to be activated by being cut, but only needs to "deform" itself to complete the task. In addition, it does not require a ring to be closed to make holes, and the holes it forms are flexible and vary in size.

　　This makes everyone more curious about its appearance.

　　In 2000, scientists from the National Institutes of Health analyzed the monomer structure of BAX. Everyone saw what BAX looks like in the standby state in the cytoplasm. Later, based on the research on activated BAX, everyone believed that BAX would "club together" on the outer membrane of the mitochondria, using dimers as the basic unit.

　　From this they speculated that BAX polymers have the same basic repeat units.

　　Just like beads, beads are connected in strings. So what does this "bead" look like? Is it the "dimer" that scientists thought before?

　　no.

　　Researchers found that the basic repeat units of BAX are much more complex than dimers.

　　We call the activated single BAX one promethorum, and the promethorum has two different appearances, called type-I and type-II. The asymmetric dimer formed by these two promes of different appearances is further dimerized to form a complete "bead".

　　In other words, each basic repeat unit actually contains 4 BAX protomers.

　　From this they speculated that BAX polymers have the same basic repeat units.

　　Just like beads, beads are connected in strings. So what does this "bead" look like? Is it the "dimer" that scientists thought before?

　　no.

　　Researchers found that the basic repeat units of BAX are much more complex than dimers.

　　We call the activated single BAX one promethorum, and the promethorum has two different appearances, called type-I and type-II. The asymmetric dimer formed by these two promes of different appearances is further dimerized to form a complete "bead".

　　In other words, each basic repeat unit actually contains 4 BAX protomers.

　　In the figure above, there are quadrilaterals, pentagons, hexagons, and heptagons, which are composed of 16, 20, 24, and 28 BAX protomers, respectively. The amount of BAX required for such loop/hole formation is also unknown before.

　　When researchers tried to remove or "modify" the BAX protein, BAX had more or less problems when performing the "God of Death" duties, either unable to form a formation or no longer able to punch holes.

　　At this point, the researchers not only revealed what the basic repeat units of BAX polymer look like, but also determined that linear, arc-shaped, and ring-shaped BAX polymers all adopt the same assembly method, but also proved the important role of the formation of BAX polymers in cell apoptosis.

　　Imagine if we could interfere with the process of BAX's "array formation", could we regulate the life and death of cells?

　　From this perspective, this study not only answers the questions that have plagued the academic community for decades, but also provides important biological information for understanding the occurrence of apoptosis, but also provides a new perspective for future research on diseases related to apoptosis.