Wang Chunyu
Biology Department and the Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, 110 8th St., Troy, NY12180, USA.
Protein Pept Lett. 2011 Apr;18(4):354-61. doi: 10.2174/092986611794653969.
Aβ is widely recognized as a key molecule in Alzheimer's disease, causing neurotoxicity through Aβ aggregates such as Aβ oligomers and fibrils. Aβ40 and Aβ42, composed of 40 and 42 residues, respectively, are the major Aβ species in human brain. Aβ42 aggregates much faster than Aβ40 but the mechanism of such difference in aggregation propensity is poorly understood. Using NMR spin relaxation, we have shown that Aβ40 and Aβ42 monomers have different dynamics in both backbone and sidechain on the ps-ns time scale. Aβ42 is more rigid in C-terminus in both backbone and sidechain while Aβ40 has more rigid methyl groups in the central hydrophobic cluster (CHC: Aβ17-21). These observations are consistent with differences in the major conformations of Aβ40 and Aβ42 monomers derived from replica exchange MD (REMD). To further demonstrate the relevance of dynamics in aggregation mechanism, a perturbation was introduced to Aβ42 in the form of M35 oxidation. After M35 side chain oxidation to sulfoxide, Aβ42 experiences Aβ40-like changes in dynamics. At the same time, M35 oxidation causes dramatic reduction in Aβ42 aggregation rate. These data have thus established an important role for protein dynamics in the mechanism of Aβ aggregation.
淀粉样β蛋白（Aβ）被广泛认为是阿尔茨海默病中的关键分子，它通过Aβ聚集体（如Aβ寡聚体和纤维）引起神经毒性。分别由40个和42个残基组成的Aβ40和Aβ42是人类大脑中的主要Aβ种类。Aβ42的聚集速度比Aβ40快得多，但这种聚集倾向差异的机制却知之甚少。通过核磁共振自旋弛豫，我们发现Aβ40和Aβ42单体在皮秒到纳秒的时间尺度上，主链和侧链的动力学都有所不同。Aβ42在主链和侧链的C末端更刚性，而Aβ40在中央疏水簇（CHC：Aβ17 - 21）中有更多刚性甲基。这些观察结果与来自复制交换分子动力学（REMD）的Aβ40和Aβ42单体主要构象的差异一致。为了进一步证明动力学在聚集机制中的相关性，以M35氧化的形式对Aβ42进行了扰动。M35侧链氧化为亚砜后，Aβ42的动力学发生了类似Aβ40的变化。同时，M35氧化导致Aβ42聚集速率显著降低。因此，这些数据确立了蛋白质动力学在Aβ聚集机制中的重要作用。
