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Humanin decreases mitochondrial membrane permeability by inhibiting the membrane association and oligomerization of Bax and Bid proteins.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2018-Jun-01 , DOI: 10.1038/aps.2017.169
Ze-wei Ma , Dong-xiang Liu

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 Aβ 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 Förster 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.

中文翻译:

Humanin通过抑制Bax和Bid蛋白的膜缔合和寡聚来降低线粒体膜的通透性。

Humanin(HN)是从患有阿尔茨海默氏病(AD)的患者的大脑中鉴定出的24个残基肽。已发现HN可以防止由Aβ肽或家族性AD突变基因的转染引起的神经元损伤。为了阐明HN神经保护的分子机制,我们探索了HN对Bax或Bid与脂质双层的结合及其在膜中的低聚的影响。通过使用单分子荧光和Förster共振能量转移技术,我们发现Bax主要以脂质双层中的单体,二聚体和四聚体形式存在,而截短的Bid(tBid)增强了Bax的膜缔合和四聚化。HN(100 nmol / L)抑制Bax与双层的自缔合和tBid激活的缔合,并显着降低了Bax在四聚体中的比例。此外,HN抑制了Bid易位至脂质双层。HN可以在溶液中或在膜中与Bax和Bid结合。但是,HN无法将蛋白质拉出膜。基于这些结果,我们提出HN与溶液中的Bax和cBid结合并抑制其向膜的移位。同时,HN与膜结合的Bax和tBid相互作用,从而阻止细胞溶质Bax的募集及其在膜中的低聚。这样,HN抑制了线粒体外膜中Bax孔的形成,并抑制了细胞色素c的释放和线粒体依赖性细胞凋亡。HN无法将蛋白质拉出膜。基于这些结果,我们提出HN与溶液中的Bax和cBid结合并抑制其向膜的移位。同时,HN与膜结合的Bax和tBid相互作用,从而阻止了胞质Bax的募集及其在膜中的低聚。这样,HN抑制了线粒体外膜中Bax孔的形成,并抑制了细胞色素c的释放和线粒体依赖性细胞凋亡。HN无法将蛋白质拉出膜。根据这些结果,我们建议HN与溶液中的Bax和cBid结合并抑制其向膜的移位。同时,HN与膜结合的Bax和tBid相互作用,从而阻止细胞溶质Bax的募集及其在膜中的低聚。这样,HN抑制了线粒体外膜中Bax孔的形成,并抑制了细胞色素c的释放和线粒体依赖性细胞凋亡。
更新日期:2017-12-21
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