Conformational States of the Cytoprotective Protein Bcl-xL
Conformational States of the Cytoprotective Protein Bcl-xL
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DOI：
10.1016/j.bpj.2020.08.014
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发表时间：
2020-10-06
影响因子：
3.4
通讯作者：
Marassi, Francesca M.
中科院分区：
文献类型：
--
作者：
Ryzhov, Pavel;Tian, Ye;Marassi, Francesca M.
Bcl-xL是细胞凋亡的主要抑制剂，细胞凋亡是程序性细胞死亡的基本稳态过程，在整个进化过程中高度保守。由于Bcl-xL在癌症中发挥着重要作用，因此它是抗癌治疗和旨在了解其结构和活性的研究的主要靶点。尽管Bcl-xL主要在细胞膜内活跃，但大多数研究都集中在缺乏膜锚定c末端尾部和内在无序环的蛋白质的可溶性形式上，这导致了对蛋白质生物活性的碎片化看法。在这里，我们描述了全长Bcl-xL的构象。利用核磁共振波谱、分子动力学模拟和等温滴定量热法，我们展示了这三种结构元素如何影响蛋白质在可溶性和膜锚定状态下的结构、动力学和配体结合活性。这些综合数据提供了关于蛋白质功能的分子基础的信息，以及对其复杂分子机制的看法。
Bcl-xL is a major inhibitor of apoptosis, a fundamental homeostatic process of programmed cell death that is highly conserved across evolution. Because it plays prominent roles in cancer, Bcl-xL is a major target for anticancer therapy and for studies aimed at understanding its structure and activity. Although Bcl-xL is active primarily at intracellular membranes, most studies have focused on soluble forms of the protein lacking both the membrane-anchoring C-terminal tail and the intrinsically disordered loop, and this has resulted in a fragmented view of the protein's biological activity. Here, we describe the conformation of full-length Bcl-xL. Using NMR spectroscopy, molecular dynamics simulations, and isothermal titration calorimetry, we show how the three structural elements affect the protein's structure, dynamics, and ligand-binding activity in both its soluble and membrane-anchored states. The combined data provide information about the molecular basis for the protein's functionality and a view of its complex molecular mechanisms.