Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Linde Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Commun. 2021 Aug 13;12(1):4932. doi: 10.1038/s41467-021-25200-7.
BAX is a pro-apoptotic member of the BCL-2 family, which regulates the balance between cellular life and death. During homeostasis, BAX predominantly resides in the cytosol as a latent monomer but, in response to stress, transforms into an oligomeric protein that permeabilizes the mitochondria, leading to apoptosis. Because renegade BAX activation poses a grave risk to the cell, the architecture of BAX must ensure monomeric stability yet enable conformational change upon stress signaling. The specific structural features that afford both stability and dynamic flexibility remain ill-defined and represent a critical control point of BAX regulation. We identify a nexus of interactions involving four residues of the BAX core α5 helix that are individually essential to maintaining the structure and latency of monomeric BAX and are collectively required for dimeric assembly. The dual yet distinct roles of these residues reveals the intricacy of BAX conformational regulation and opportunities for therapeutic modulation.
BAX 是 BCL-2 家族的一种促凋亡成员，它调节细胞生死的平衡。在体内平衡时，BAX 主要以潜伏单体的形式存在于细胞质中，但在受到应激时，它会转化为寡聚体蛋白，使线粒体通透，导致细胞凋亡。由于叛逆的 BAX 激活对细胞构成严重威胁，因此 BAX 的结构必须确保单体的稳定性，同时在应激信号作用下能够发生构象变化。提供稳定性和动态灵活性的具体结构特征仍不清楚，这是 BAX 调节的一个关键控制点。我们确定了涉及 BAX 核心 α5 螺旋的四个残基的相互作用网络，这些残基单独对于维持单体 BAX 的结构和潜伏性至关重要，并且对于二聚体组装也是必需的。这些残基的双重但又不同的作用揭示了 BAX 构象调节的复杂性和治疗调节的机会。
