Bcl-2 changes conformation to inhibit Bax oligomerization
Bcl-2 changes conformation to inhibit Bax oligomerization
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DOI：
10.1038/sj.emboj.7601126
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发表时间：
2006-06-07
期刊：
影响因子：
11.4
通讯作者：
Andrews, David W.
中科院分区：
文献类型：
--
作者：
Dlugosz, Paulina J.;Billen, Lieven P.;Andrews, David W.
Bcl2通过调节线粒体释放细胞色素c和其他蛋白质来抑制细胞凋亡。Bax的寡聚通过穿透线粒体膜促进细胞死亡。在转基因细胞和分离的线粒体中，在TBID和Bax等凋亡激动剂的作用下，线粒体膜上的构象发生了改变，而非非活化点突变体Bcl2-G145A和Bcl2-V159D。含有两个半胱氨酸的突变体(Bc l-2-S105C/E152C)只在还原环境中才有活性，该突变体预计会导致二硫键，从而抑制α5-a 6螺旋的流动性。因此，Bcl2必须改变构象，以抑制TBID诱导的整膜Bax单体和小寡聚的齐聚。构象改变的Bcl2隔离了Bax的整体膜形式。如果Bax过多，细胞凋亡就会恢复，因为Bcl2被构象变化所消耗，并与Bax形成复合体。因此，通过改变线粒体膜上的构象来结合膜上插入的Bax单体，阻止Bax的高效寡聚，Bcl2发挥着抑制线粒体通透性的作用。
Bcl-2 inhibits apoptosis by regulating the release of cytochrome c and other proteins from mitochondria. Oligomerization of Bax promotes cell death by permeabilizing the outer mitochondrial membrane. In transfected cells and isolated mitochondria, Bcl-2, but not the inactive point mutants Bcl-2-G145A and Bcl-2-V159D, undergoes a conformation change in the mitochondrial membrane in response to apoptotic agonists such as tBid and Bax. A mutant Bcl-2 with two cysteines introduced at positions predicted to result in a disulfide bond that would inhibit the mobility of alpha 5-alpha 6 helices (Bcl-2-S105C/E152C) was only active in a reducing environment. Thus, Bcl-2 must change the conformation to inhibit tBid-induced oligomerization of integral membrane Bax monomers and small oligomers. The conformationally changed Bcl-2 sequesters the integral membrane form of Bax. If Bax is in excess, apoptosis resumes as Bcl-2 is consumed by the conformational change and in complexes with Bax. Thus, Bcl-2 functions as an inhibitor of mitochondrial permeabilization by changing conformation in the mitochondrial membrane to bind membrane-inserted Bax monomers and prevent productive oligomerization of Bax.