Conformational changes in amyloid-beta (12-28) alloforms studied using action-FRET, IMS and molecular dynamics simulations.
Conformational changes in amyloid-beta (12-28) alloforms studied using action-FRET, IMS and molecular dynamics simulations.
复制标题
DOI：
10.1039/c5sc01463h
复制
发表时间：
2015-08-01
期刊：
影响因子：
8.4
通讯作者：
Dugourd P
中科院分区：
文献类型：
--
作者：
Daly S;Kulesza A;Poussigue F;Simon AL;Choi CM;Knight G;Chirot F;MacAleese L;Antoine R;Dugourd P
通过多种技术研究了两种淀粉样蛋白β突变体的气相构象，以阐明不同聚集行为的起源。淀粉样β蛋白（Aβ）的小寡聚体已被认为是导致阿尔茨海默病的神经毒性剂，并且特别是包含氨基酸L17至A21的疏水核心区中的突变对聚集体形成的倾向具有很大影响。已经表明，Aβ的F19 P同种异型形成小聚集体，但不会继续形成大的原纤维和斑块。为了理解这种行为的起源，通过结合作用FRET、离子迁移谱（IMS）和分子动力学模拟研究了淀粉样蛋白β的野生型12-28片段及其F19 P同种异型物的不同电荷状态的气相构象。实验和理论的行动FRET效率和碰撞截面的比较允许确定的最低能量的构象家庭为每个异形体和电荷状态。对于这两种异形体，发现在3+和4+电荷状态之间存在从球状到螺旋结构的变化。额外的质子化以产生5+和6+电荷状态引起该螺旋基序的解折叠，其中野生异型显示β-转角样基序和F19 P异型无规卷曲基序。在野生型中存在螺旋向β-转角结构转变，而在F19 P异型中不存在，这可能有助于阐明两种异型的聚集行为的巨大差异的起源。
The gas phase conformations of two amyloid beta mutants are studied by multiple techniques to elucidate the origin of the different aggregation behaviour. Small oligomers of the amyloid beta protein (Aβ) have been implicated as the neurotoxic agent leading to Alzheimer's disease, and in particular mutations in the hydrophobic core region comprising amino acids L17 to A21 have a large influence on the propensity for aggregate formation. It has been shown that the F19P alloform of Aβ forms small aggregates, but does not proceed to form large fibrils and plaques. In order to understand the origin of this behavior, the gas phase conformations for the different charge states of the wild-type 12–28 fragment of the amyloid beta and its F19P alloform were studied by a combination of action-FRET, ion-mobility spectrometry (IMS) and molecular dynamics simulations. Comparison of the experimental and theoretical action-FRET efficiencies and collision cross sections allowed the determination of the lowest energy conformational family for each alloform and charge state. For both alloforms, it was found that there is a change from globular to helical structure between the 3+ and 4+ charge states. Additional protonation to give 5+ and 6+ charge states caused unfolding of this helical motif, with the wild alloform showing β-turn like motifs and the F19P alloform random coil motifs. The presence of the helical to β-turn structural transition in the wild, but not the F19P, alloform may help to elucidate the origin of the large difference in aggregation behavior of the two alloforms.
登录
查看更多内容
影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
15
作者：
Canon, Francis;Ballivian, Renaud;Dugourd, Philippe
通讯作者：
Dugourd, Philippe
影响因子：
15
作者：
Bernstein, SL;Wyttenbach, T;Bowers, MT
通讯作者：
Bowers, MT
影响因子：
3.3
作者：
Mandal, Paulami;Eremina, Nadejda;Barth, Andreas
通讯作者：
Barth, Andreas
影响因子：
15
作者：
Jarvet, J;Damberg, P;Gräslund, A
通讯作者：
Gräslund, A