The N-terminal end of Bax contains a mitochondrial-targeting signal
The N-terminal end of Bax contains a mitochondrial-targeting signal
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DOI：
10.1074/jbc.m208955200
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发表时间：
2003-03-28
影响因子：
4.8
通讯作者：
Vallette, FM
中科院分区：
文献类型：
--
作者：
Cartron, PF;Priault, M;Vallette, FM
Baxα是BCL-2家族中的促凋亡成员，从胞浆到线粒体的转位是细胞凋亡过程中的中心事件。我们在这里报道，Baxα的N端(NT)末端包含其第一个α螺旋(Halpha1)，在哺乳动物和酵母中都是一个功能性的线粒体寻址信号。新描述的bax变种bax psi也得到了类似的结果，该变种缺少bax a的前20个氨基酸，并与线粒体密切相关。Halpha1的缺失削弱了Bax psi与线粒体的结合，而包含Halpha1的Baxα的N端与胞浆蛋白的融合导致了嵌合蛋白在无细胞实验和体外实验中与线粒体的结合。更重要的是，与线粒体结合的嵌合蛋白抑制了Bax psi与线粒体的相互作用以及Bax的促凋亡特性。Halpha1的突变抑制了Baxα和Bax psi转位到线粒体，也阻止了随后的细胞凋亡执行阶段的激活。相反，C末端的缺失似乎不影响Bax a和Bax psi线粒体的寻址。综上所述，我们的结果表明，Bax通过其NT靶向线粒体，从而通过一条bcl2家族成员所特有的途径。
The translocation of Bax alpha, a pro-apoptotic member of the BCL-2 family from the cytosol to mitochondria, is a central event of the apoptotic program. We report here that the N-terminal (NT) end of Bax alpha, which contains its first alpha helix (Halpha1), is a functional mitochondrial-addressing signal both in mammals and in yeast. Similar results were obtained with a newly described variant of Bax called Bax psi, which lacks the first 20 amino acids of Bax a and is constitutively associated with mitochondria. Deletion of Halpha1 impairs the binding of Bax psi to mitochondria, whereas a fusion of the N terminus of Bax alpha, which contains Halpha1 with a cytosolic protein, results in the binding of the chimeric proteins to mitochondria both in a cell-free assay and in vitro. More importantly, the mitochondria-bound chimeric proteins inhibit the interaction of Bax psi with mitochondria as well as Bax-apoptogenic properties. The mutations of the Halpha1, which inhibit Bax alpha and Bax psi translocation to mitochondria, also block the subsequent activation of the execution phase of apoptosis. Conversely, a deletion of the C terminus does not appear to influence Bax a and Bax psi mitochondrial addressing. Taken together, our results suggest that Bax is targeted to mitochondria by its NT and thus through a pathway that is unique for a member of the BCL-2 family.