Molecular basis for chirality-regulated Aβ self-assembly and receptor recognition revealed by ion mobility-mass spectrometry
Molecular basis for chirality-regulated Aβ self-assembly and receptor recognition revealed by ion mobility-mass spectrometry
复制标题
DOI：
10.1038/s41467-019-12346-8
复制
发表时间：
2019-11-06
影响因子：
16.6
通讯作者：
Li, Lingjun
中科院分区：
文献类型：
--
作者：
Li, Gongyu;DeLaney, Kellen;Li, Lingjun
尽管人们对阿尔茨海默病(AD)的发病机制进行了广泛的探索，并在AD药物开发上投入了巨大的资金，但缺乏有效的疾病修饰疗法以及AD发病过程的复杂性表明，迫切需要对替代AD药物靶点进行进一步的深入了解。在这里，我们关注截短的淀粉样β蛋白(Aβ)的手性效应，并为抗原表位区域特异性、手性调节的Aβ片段的自组装及其对受体识别的潜在影响提供进一步的结构和分子证据。多维离子迁移率-质谱仪(IM-MS)分析平台和溶液动力学分析揭示了差异Aβ片段手性化学的全面结构和分子基础，包括手性AβN端和C端片段在受体识别中的差异和协同作用。我们的方法也适用于许多其他系统，结果可能有助于基于靶向D-异构化Aβ而不是天然L-Aβ的新型AD治疗策略的潜在开发。
Despite extensive efforts on probing the mechanism of Alzheimer's disease (AD) and enormous investments into AD drug development, the lack of effective disease-modifying therapeutics and the complexity of the AD pathogenesis process suggest a great need for further insights into alternative AD drug targets. Herein, we focus on the chiral effects of truncated amyloid beta (A beta) and offer further structural and molecular evidence for epitope region-specific, chirality-regulated A beta fragment self-assembly and its potential impact on receptor-recognition. A multidimensional ion mobility-mass spectrometry (IM-MS) analytical platform and in-solution kinetics analysis reveal the comprehensive structural and molecular basis for differential A beta fragment chiral chemistry, including the differential and cooperative roles of chiral A beta N-terminal and C-terminal fragments in receptor recognition. Our method is applicable to many other systems and the results may shed light on the potential development of novel AD therapeutic strategies based on targeting the D-isomerized A beta, rather than natural L-A beta.