...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The FEBS journal >Cholesterol-containing lipid nanodiscs promote an alpha-synuclein binding mode that accelerates oligomerization
【24h】

Cholesterol-containing lipid nanodiscs promote an alpha-synuclein binding mode that accelerates oligomerization

机译：含胆固醇的脂质纳米DISC促进α-突触核蛋白结合模式，其加速寡聚化

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Dysregulation of the biosynthesis of cholesterol and other lipids has been implicated in many neurological diseases, including Parkinson's disease. Misfolding of alpha-synuclein (alpha-Syn), the main actor in Parkinson's disease, is associated with changes in a lipid environment. However, the exact molecular mechanisms underlying cholesterol effect on alpha-Syn binding to lipids as well as alpha-Syn oligomerization and fibrillation remain elusive, as does the relative importance of cholesterol compared to other factors. We probed the interactions and fibrillation behaviour of alpha-Syn using styrene-maleic acid nanodiscs, containing zwitterionic and anionic lipid model systems with and without cholesterol. Surface plasmon resonance and thioflavin T fluorescence assays were employed to monitor alpha-Syn binding, as well as fibrillation in the absence and presence of membrane models.H-1-N-15-correlated NMR was used to monitor the fold of alpha-Syn in response to nanodisc binding, determining individual residue apparent affinities for the nanodisc-contained bilayers. The addition of cholesterol inhibited alpha-Syn interaction with lipid bilayers and, however, significantly promoted alpha-Syn fibrillation, with a more than a 20-fold reduction of lag times before fibrillation onset. When alpha-Syn bilayer interactions were analysed at an individual residue level by solution-state NMR, we observed two different effects of cholesterol. In nanodiscs made of DOPC, the addition of cholesterol modulated the NAC part of alpha-Syn, leading to stronger interaction of this region with the lipid bilayer. In contrast, in the nanodiscs comprising DOPC, DOPE and DOPG, the NAC part was mostly unaffected by the presence of cholesterol, while the binding of the N and the C termini was both inhibited.
机译：胆固醇和其他脂质生物合成的失调与许多神经系统疾病有关，包括帕金森病。阿尔法-突触核蛋白（alpha-Syn）是帕金森病的主要因素，其错误折叠与脂质环境的变化有关。然而，与其他因素相比，胆固醇对α-Syn与脂质结合、α-Syn寡聚和纤颤的确切分子机制以及胆固醇的相对重要性仍不清楚。我们使用苯乙烯-马来酸纳米盘（含有含和不含胆固醇的两性离子和阴离子脂质模型系统）研究了α-Syn的相互作用和纤颤行为。表面等离子体共振和硫黄素T荧光分析用于监测α-Syn结合，以及在没有和存在膜模型的情况下的纤颤。H-1-N-15相关NMR用于监测α-Syn的折叠对纳米盘结合的反应，确定含有纳米盘的双层膜的单个残基表观亲和力。胆固醇的加入抑制了α-Syn与脂质双层的相互作用，但显著促进了α-Syn纤颤，纤颤开始前的滞后时间缩短了20倍以上。当通过溶液状态NMR在单个残基水平上分析α-Syn双层相互作用时，我们观察到胆固醇的两种不同影响。在由DOPC制成的纳米盘中，胆固醇的加入调节了α-Syn的NAC部分，导致该区域与脂质双层的相互作用更强。相比之下，在包含DOPC、DOPE和DOPG的纳米盘中，NAC部分大部分不受胆固醇的影响，而N端和C端的结合均受到抑制。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号