Humanin decreases mitochondrial membrane permeability by inhibiting the membrane association and oligomerization of Bax and Bid proteins
Humanin decreases mitochondrial membrane permeability by inhibiting the membrane association and oligomerization of Bax and Bid proteins
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护脑素通过抑制 Bax 和 Bid 蛋白的膜缔合和寡聚来降低线粒体膜通透性
DOI：
10.1038/aps.2017.169
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发表时间：
2018-06-01
影响因子：
8.2
通讯作者：
Liu, Dong-xiang
中科院分区：
文献类型：
--
作者：
Ma, Ze-wei;Liu, Dong-xiang
Humanin（HN）是从阿尔茨海默病（AD）患者的脑中鉴定的24个残基的肽。已发现HN保护免受由A β肽或家族性AD突变基因转染引起的神经元损伤。为了阐明HN神经保护作用的分子机制，我们探讨了HN对Bax或Bid与脂双层的缔合及其在膜中的寡聚化的影响。通过单分子荧光和Forster共振能量转移技术，我们发现Bax主要以单体、二聚体和四聚体的形式存在于脂质双层中，而截短的Bid（tBid）增强了Bax的膜结合和四聚化。HN（100 nmol/L）可抑制Bax与细胞双层的自结合和tBid激活的结合，并显著降低Bax在四聚体中的比例。此外，HN抑制Bid转运到脂双层。HN与Bax和Bid在溶液中或膜中均能结合。然而，HN不能将蛋白质拉出膜。基于这些结果，我们建议，HN结合到Bax和cBid在溶液中，并抑制其易位到膜。同时，HN与膜结合的Bax和tBid相互作用，阻止胞浆Bax的募集及其在膜中的寡聚化。通过这种方式，HN抑制线粒体外膜中Bax孔的形成，并抑制细胞色素c的释放和细胞色素a依赖的细胞凋亡。
Humanin (HN) is a 24-residue peptide identified from the brain of a patient with Alzheimer's disease (AD). HN has been found to protect against neuronal insult caused by A beta peptides or transfection of familial AD mutant genes. In order to elucidate the molecular mechanisms of HN neuroprotection, we explored the effects of HN on the association of Bax or Bid with lipid bilayers and their oligomerization in the membrane. By using single-molecule fluorescence and Forster resonance energy transfer techniques, we showed that Bax was mainly present as monomers, dimers and tetramers in lipid bilayers, while truncated Bid (tBid) enhanced the membrane association and tetramerization of Bax. HN (100 nmol/L) inhibited the self-association and tBid-activated association of Bax with the bilayers, and significantly decreased the proportion of Bax in tetramers. Furthermore, HN inhibited Bid translocation to lipid bilayers. HN could bind with Bax and Bid either in solution or in the membrane. However, HN could not pull the proteins out of the membrane. Based on these results, we propose that HN binds to Bax and cBid in solution and inhibits their translocation to the membrane. Meanwhile, HN interacts with the membrane-bound Bax and tBid, preventing the recruitment of cytosolic Bax and its oligomerization in the membrane. In this way, HN inhibits Bax pore formation in mitochondrial outer membrane and suppresses cytochrome c release and mitochondria-dependent apoptosis.