Still embedded together binding to membranes regulates Bcl-2 protein interactions.
Still embedded together binding to membranes regulates Bcl-2 protein interactions.
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DOI：
10.1038/onc.2010.283
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发表时间：
2010-09-23
期刊：
影响因子：
8
通讯作者：
Andrews DW
中科院分区：
文献类型：
--
作者：
Leber B;Lin J;Andrews DW
细胞凋亡的失调是肿瘤发生的关键步骤，也是导致肿瘤治疗抵抗的重要因素。许多不同的细胞死亡信号汇聚在线粒体外膜的通透性上，线粒体膜的通透性受Bcl2蛋白家族的控制。随着第一代抑制Bcl-2家族蛋白相互作用的小分子作为抗癌剂进入临床试验，这一步骤的重要性变得越来越重要。Bcl2家族可分为三类：受各种形式的细胞应激激活的BH3蛋白，介导线粒体膜通透性的Bax和Bak蛋白，以及抑制蛋白如Bcl2和Bclxl。最近提出的Embedded Together模型强调了这样一个事实，即不同类别的Bcl-2家族成员之间的许多调控相互作用发生在细胞内的膜上，与膜的结合导致动态地决定功能的蛋白质的构象变化。在此背景下，最近的研究结果表明，Bclxl的功能是显性负Bax，这一概念解决了Bclxl和Bax结构相似但功能相反的悖论。我们还表明，允许Bax插入线粒体膜外膜的构象变化是Bax激活的多步骤过程中的限速步骤。然而，研究活化的Bax或Bak作为单体和作为介导膜通透性的低聚结构的组成部分的结构是世界各地许多实验室正在进行的研究(和争议)的焦点。
The dysregulation of apoptosis is a key step in developing tumours, and mediates resistance to cancer therapy. Many different signals for cell death converge on permeabilization of the outer mitochondrial membrane, which is controlled by the Bcl-2 family of proteins. The importance of this step is becoming increasingly relevant as the first generation of small molecules that inhibit the interaction of Bcl-2 family proteins enters clinical trials as anticancer agents. The Bcl-2 family can be divided into three classes: BH3-only proteins that are activated by various forms of cellular stress, Bax and Bak proteins that mediate mitochondrial membrane permeabilization, and inhibitory proteins such as Bcl-2 and Bcl-XL. The recently proposed embedded together model emphasizes the fact that many of the regulatory interactions between different classes of Bcl-2 family members occur at intracellular membranes, and binding to membranes causes conformational changes in the proteins that dictate functions in a dynamic manner. Within this context, recent results indicate that Bcl-XL functions as a dominant-negative Bax, a concept that resolves the paradox of similar structures but opposite functions of Bcl-XL and Bax. We have also shown that the conformational change that allows Bax to insert into the outer mitochondrial membrane is the rate-limiting step in the multistep process of Bax activation. Nevertheless, investigating the structure of activated Bax or Bak as monomers and as components of the oligomeric structures that mediate membrane permeabilization is the focus of ongoing research (and controversy) at many laboratories worldwide.
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