BAX and BAK are essential mediators of intrinsic apoptosis that permeabilize the mitochondrial outer membrane. BAX activation requires its translocation from cytosol to mitochondria where conformational changes cause its oligomerization. To better understand the critical step of translocation, we examined its blockade by mutation near the C terminus (P168G) or by antibody binding near the N terminus. Similarities in the crystal structures of wild-type and BAX P168G but significant other differences suggest that cytosolic BAX exists as an ensemble of conformers, and that the distribution of conformers within the ensemble determines the different functions of wild-type and mutant proteins. We also describe the structure of BAX in complex with an antibody, 3C10, that inhibits cytosolic BAX by limiting exposure of the membrane-associating helix α9, as does the P168G mutation. Our data for both means of BAX inhibition argue for an allosteric model of BAX regulation that derives from properties of the ensemble of conformers.

中文翻译：

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Bax的合奏特性决定其功能。

BAX和BAK是内在凋亡的重要介质，可穿透线粒体外膜。BAX激活需要将其从胞质溶胶转移到线粒体，在那里构象变化会导致其寡聚。为了更好地理解易位的关键步骤，我们检查了C末端（P168G）附近的突变或N末端附近的抗体结合对它的阻滞作用。野生型和BAX P168G的晶体结构相似，但其他显着差异表明胞质BAX作为构象体集合存在，而构象体中的构象子分布决定了野生型和突变蛋白的不同功能。我们还描述了BAX与3C10抗体复合物的结构，该抗体可通过限制与膜相关的螺旋α9的暴露来抑制胞质BAX。和P168G突变一样。我们关于BAX抑制的两种方法的数据都证明了一种BAX调节的变构模型，该模型源自构象体集合的性质。