Miller Yifat, Ma Buyong, Nussinov Ruth
Center for Cancer Research Nanobiology Program, National Cancer Institute-Frederick, Frederick, Maryland, USA.
Biophys J. 2009 Aug 19;97(4):1168-77. doi: 10.1016/j.bpj.2009.05.042.
Abeta(17-42) (so-called p3) amyloid is detected in vivo in the brains of individuals with Alzheimer's disease or Down's syndrome. We investigated the polymorphism of Abeta(17-42) oligomers based on experimental data from steady-state NMR measurements, electron microscopy, two-dimensional hydrogen exchange, and mutational studies, using all-atom molecular-dynamics simulation with explicit solvent. We assessed the structural stability and the populations. Our results suggest that conformational differences in the U-turn of Abeta(17-42) lead to polymorphism in beta-sheet registration and retention of an ordered beta-strand organization at the termini. Further, although the parallel Abeta(17-42) oligomer organization is the most stable of the conformers investigated here, different antiparallel Abeta(17-42) organizations are also stable and compete with the parallel architectures, presenting a polymorphic population. In this study we propose that 1), the U-turn conformation is the primary factor leading to polymorphism in the assembly of Abeta(17-42) oligomers, and is also coupled to oligomer growth; and 2), both parallel Abeta(17-42) oligomers and an assembly of Abeta(17-42) oligomers that includes both parallel and antiparallel organizations contribute to amyloid fibril formation. Finally, since a U-turn motif generally appears in amyloids formed by full proteins or long fragments, and since to date these have been shown to exist only in parallel architectures, our results apply to a broad range of oligomers and fibrils.
在患有阿尔茨海默病或唐氏综合征的个体大脑中，可在体内检测到β淀粉样蛋白（17 - 42）（即所谓的p3）。我们基于稳态核磁共振测量、电子显微镜、二维氢交换和突变研究的实验数据，使用含显式溶剂的全原子分子动力学模拟，研究了β淀粉样蛋白（17 - 42）寡聚体的多态性。我们评估了结构稳定性和群体分布。我们的结果表明，β淀粉样蛋白（17 - 42）的U型转弯处的构象差异导致β折叠排列的多态性以及末端有序β链组织的保留。此外，尽管平行的β淀粉样蛋白（17 - 42）寡聚体组织在此处研究的构象中是最稳定的，但不同的反平行β淀粉样蛋白（17 - 42）组织也很稳定，并与平行结构竞争，呈现出多态性群体。在本研究中，我们提出：1）U型转弯构象是导致β淀粉样蛋白（17 - 42）寡聚体组装多态性的主要因素，并且还与寡聚体生长相关；2）平行的β淀粉样蛋白（17 - 42）寡聚体以及包括平行和反平行组织的β淀粉样蛋白（17 - 42）寡聚体组装都有助于淀粉样纤维的形成。最后，由于U型转弯基序通常出现在由完整蛋白质或长片段形成的淀粉样蛋白中，并且迄今为止已证明这些仅存在于平行结构中，所以我们的结果适用于广泛的寡聚体和纤维。
