Bak Activation for Apoptosis Involves Oligomerization of Dimers via Their α6 Helices
Bak Activation for Apoptosis Involves Oligomerization of Dimers via Their α6 Helices
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DOI：
10.1016/j.molcel.2009.11.008
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发表时间：
2009-11-25
期刊：
影响因子：
16
通讯作者：
Kluck, Ruth M.
中科院分区：
文献类型：
--
作者：
Dewson, Grant;Kratina, Tobias;Kluck, Ruth M.
凋亡的关键步骤是Bcl-2相关巴克的寡聚化。我们最近报道，它的寡聚化起始于一个暴露的BH 3结构域插入到另一个巴克单体的沟中。我们现在报告，由此产生的BH 3：沟二聚体可以转化为较大的寡聚体，通过α 6螺旋之间的界面渗透线粒体。位于α 6的半胱氨酸残基只能在凋亡信号传导后交联。位于两个界面的半胱氨酸确定了BH 3：凹槽二聚体是对称的，并且α 6：α 6界面可以将这些二聚体连接成含有至少18个巴克分子的同源寡聚体。α 6中假定的锌结合位点不需要形成α 6：α 6界面，并且其在全长巴克中的突变不影响巴克构象、寡聚化或功能。我们得出结论，α 6：α 6相互作用发生在巴克寡聚化和促凋亡功能，但我们没有发现证据表明，锌结合到该接口调节凋亡。
A pivotal step toward apoptosis is oligomerization of the Bcl-2 relative Bak. We recently reported that its oligomerization initiates by insertion of an exposed BH3 domain into the groove of another Bak monomer. We now report that the resulting BH3:groove dimers can be converted to the larger oligomers that permeabilize mitochondria by an interface between alpha 6 helices. Cysteine residues placed in alpha 6 could be crosslinked only after apoptotic signaling. Cysteines placed at both interfaces established that the BH3:groove dimer is symmetric and that the alpha 6:alpha 6 interface can link these dimers into homo-oligomers, containing at least 18 Bak molecules. A putative zinc-binding site in alpha 6 was not required to form the alpha 6:alpha 6 interface, and its mutation in full-length Bak did not affect Bak conformation, oligomerization, or function. We conclude that alpha 6:alpha 6 interaction occurs during Bak oligomerization and proapoptotic function, but we find no evidence that zinc binding to that interface regulates apoptosis.