van Delft Mark F, Huang David C S
The Walter and Eliza Hall Institute of Medical Research, and Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia.
Cell Res. 2006 Feb;16(2):203-13. doi: 10.1038/sj.cr.7310028.
Commitment of cells to apoptosis is governed largely by protein-protein interactions between members of the Bcl-2 protein family. Its three sub-families have distinct roles: the BH3-only proteins trigger apoptosis by binding via their BH3 domain to pro-survival relatives, while the pro-apoptotic Bax and Bak have an essential downstream role involving disruption of organellar membranes and induction of caspase activation. The BH3-only proteins act as damage sensors, held inert until their activation by stress signals. Once activated, they were thought to bind promiscuously to pro-survival protein targets but unexpected selectivity has recently emerged from analysis of their interactions. Some BH3-only proteins also bind to Bax and Bak. Whether Bax and Bak are activated directly by these BH3-only proteins, or indirectly as a consequence of BH3-only proteins neutralizing their pro-survival targets is the subject of intense debate. Regardless of this, a detailed understanding of the interactions between family members, which are often selective, has notable implications for designing anti-cancer drugs to target the Bcl-2 family.
细胞对凋亡的倾向很大程度上由Bcl-2蛋白家族成员之间的蛋白质-蛋白质相互作用所调控。该家族的三个亚家族具有不同的作用：仅含BH3结构域的蛋白通过其BH3结构域与促生存相关蛋白结合来触发凋亡，而促凋亡的Bax和Bak在下游发挥关键作用，包括破坏细胞器膜和诱导半胱天冬酶激活。仅含BH3结构域的蛋白充当损伤传感器，在被应激信号激活之前处于惰性状态。一旦被激活，它们曾被认为会随机结合促生存蛋白靶点，但最近对其相互作用的分析发现了意想不到的选择性。一些仅含BH3结构域的蛋白也会与Bax和Bak结合。Bax和Bak是直接被这些仅含BH3结构域的蛋白激活，还是由于仅含BH3结构域的蛋白中和了它们的促生存靶点而间接被激活，这是激烈争论的主题。无论如何，详细了解家族成员之间通常具有选择性的相互作用，对于设计靶向Bcl-2家族的抗癌药物具有显著意义。
