Reversible random coil to β-sheet transition and the early stage of aggregation of the Aβ(12-28) fragment from the Alzheimer peptide
Reversible random coil to β-sheet transition and the early stage of aggregation of the Aβ(12-28) fragment from the Alzheimer peptide
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DOI：
10.1021/ja991167z
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发表时间：
2000-05-10
影响因子：
15
通讯作者：
Gräslund, A
中科院分区：
文献类型：
--
作者：
Jarvet, J;Damberg, P;Gräslund, A
在接近肽的等电点的pH下，通过在溶液中用高分辨率核磁共振（NMR）和圆二色性（CD）进行平行实验，在毫摩尔浓度下研究阿尔茨海默肽片段A β（12-28）。使用低温和低离子强度缓冲液的制备程序给出了具有稳定和重现性的样品。通过改变温度研究了二级结构和聚集状态的可逆变化。高温促进聚集和β-折叠诱导，而低温使平衡向低分子量部分和较少的β-折叠样结构移动。NMR扩散实验表明，占主导地位的，最低分子量的馏分是单体。随着温度的升高，残基F（20）A（21）E（22）与A β肽的所谓中心疏水片段重叠，表现出最明显的α-质子NMR二级化学位移变化，从无规卷曲向更β-折叠样结构变化。高离子强度还促进聚集和β折叠诱导。合并的光谱结果，也包括分子量估计截止过滤器，总结在一个方案中，其中单体主要是随机线圈和异构聚集的部分β-折叠形式的肽是在温度依赖性的平衡，这种情况下，对应于一个早期阶段的fibrillogenesis。
The Alzheimer peptide fragment A beta(12-28) was studied at millimolar concentration by parallel experiments with high-resolution nuclear magnetic resonance (NMR) and circular dichroism (CD) in solution at a pH close to the isoelectric point of the peptide. A preparation procedure using low temperature and low ionic strength buffer gave a sample with stable and reproducible properties. Reversible changes in secondary structure and state of aggregation were studied by variation of temperature. High-temperature promotes aggregation and beta-sheet induction, whereas low-temperature shifts the equilibrium toward low molecular weight fractions and less beta-sheet like structure. NMR diffusion experiments show that the dominating, most low molecular weight fraction is monomeric. With increasing temperature, residues F(20)A(21)E(22), overlapping with the so-called central hydrophobic segment of the A beta peptide, exhibit the most pronounced alpha-proton NMR secondary chemical shift changes from random coil toward more beta-sheet like structure. High ionic strength also promotes aggregation and beta-sheet induction. The combined spectroscopic results, including also molecular weight estimations by cutoff filters, are summarized in a scheme in which monomeric mostly random coil and heterogeneous aggregated partly beta-sheet forms of the peptide are in a temperature-dependent equilibrium, a situation which corresponds to an early stage of the fibrillogenesis.