Lovell Jonathan F, Billen Lieven P, Bindner Scott, Shamas-Din Aisha, Fradin Cecile, Leber Brian, Andrews David W
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.
Cell. 2008 Dec 12;135(6):1074-84. doi: 10.1016/j.cell.2008.11.010.
In normal circumstances, the Bcl-2 family dutifully governs when cells die. However, the rules of engagement between the pro- and antiapoptotic family members are still contested, and how Bax is transformed from a cytosolic monomer to an outer mitochondrial membrane-permeabilizing oligomer is unclear. With fluorescence techniques and an in vitro system, the combination of tBid and Bax produced dramatic membrane permeabilization. The membrane is not a passive partner in this process beause membranes are required for the protein-protein interactions to occur. Simultaneous measurements of these interactions revealed an ordered series of steps required for outer membrane permeabilization: (1) tBid rapidly binds to membranes, where (2) tBid interacts with Bax, causing (3) Bax insertion into membranes and (4) oligomerization, culminating in (5) membrane permeabilization. Bcl-XL prevents membrane-bound tBid from binding Bax. Bad releases tBid from Bcl-XL, restoring both tBid binding to Bax and membrane permeabilization.
在正常情况下，Bcl-2家族尽职地控制着细胞何时死亡。然而，促凋亡和抗凋亡家族成员之间的作用机制仍存在争议，并且Bax如何从胞质单体转变为使线粒体外膜通透的寡聚体尚不清楚。利用荧光技术和体外系统，tBid与Bax的结合产生了显著的膜通透性。在这个过程中，膜并非被动参与者，因为蛋白质-蛋白质相互作用的发生需要膜的参与。对这些相互作用的同步测量揭示了线粒体外膜通透所需的一系列有序步骤：（1）tBid迅速与膜结合，在膜上（2）tBid与Bax相互作用，导致（3）Bax插入膜中并（4）寡聚化，最终（5）导致膜通透性增加。Bcl-XL可阻止膜结合的tBid与Bax结合。Bad可将tBid从Bcl-XL中释放出来，恢复tBid与Bax的结合以及膜通透性。
