Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation.
Conformational Heterogeneity of Bax Helix 9 Dimer for Apoptotic Pore Formation.
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DOI：
10.1038/srep29502
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发表时间：
2016-07-06
影响因子：
4.6
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Liao C;Zhang Z;Kale J;Andrews DW;Lin J;Li J
Bax蛋白的抑制因子α9可在线粒体外膜上发生二聚体化，形成凋亡孔。然而，它仍然不清楚如何不同的构象的二聚体有助于在分子水平上的孔的形成。因此，我们研究了α9二聚体的各种构象状态，在一个cDNAs模型中-使用计算机模拟，并辅以α9螺旋的位点特异性诱变和交联。我们的数据不仅证实了α9稳定性和二聚化的关键膜环境，而且还揭示了不同构象状态下二聚体的不同脂质结合偏好。在我们提出的途径中，一个重要的等平行二聚体介导的构象转变被发现计算和实验验证。来自模拟和实验的确证证据表明，螺旋α9通过二聚体异质性和与特异性脂质的相互作用辅助Bax活化，最终促进凋亡调节中的蛋白脂质孔形成。
Helix α9 of Bax protein can dimerize in the mitochondrial outer membrane (MOM) and lead to apoptotic pores. However, it remains unclear how different conformations of the dimer contribute to the pore formation on the molecular level. Thus we have investigated various conformational states of the α9 dimer in a MOM model — using computer simulations supplemented with site-specific mutagenesis and crosslinking of the α9 helices. Our data not only confirmed the critical membrane environment for the α9 stability and dimerization, but also revealed the distinct lipid-binding preference of the dimer in different conformational states. In our proposed pathway, a crucial iso-parallel dimer that mediates the conformational transition was discovered computationally and validated experimentally. The corroborating evidence from simulations and experiments suggests that, helix α9 assists Bax activation via the dimer heterogeneity and interactions with specific MOM lipids, which eventually facilitate proteolipidic pore formation in apoptosis regulation.