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首页> 外文期刊>Journal of Molecular Biology >Antiparallel beta-Sheet Structure within the C-Terminal Region of 42-Residue Alzheimer's Amyloid-beta Peptides When They Form 150-kDa Oligomers
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Antiparallel beta-Sheet Structure within the C-Terminal Region of 42-Residue Alzheimer's Amyloid-beta Peptides When They Form 150-kDa Oligomers

机译：当它们形成150 kDa寡聚体时，具有42个残基的阿尔茨海默氏症淀粉样蛋白肽的C末端区域内的反平行β-Sheet结构。

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摘要

Understanding the molecular structures of amyloid-beta (A beta) oligomers and underlying assembly pathways will advance our understanding of Alzheimer's disease (AD) at the molecular level. This understanding could contribute to disease prevention, diagnosis, and treatment strategies, as oligomers play a central role in AD pathology. We have recently presented a procedure for production of 150-kDa oligomeric samples of A beta(1-42) (the 42-residue variant of the A beta peptide) that are compatible with solid-state nuclear magnetic resonance (NMR) analysis, and we have shown that these oligomers and amyloid fibrils differ in intermolecular arrangement of beta-strands. Here we report new solid-state NMR constraints that indicate antiparallel intermolecular alignment of beta-strands within the oligomers. Specifically, 150-kDa A beta(1-42) oligomers with uniform C-13 and N-15 isotopic labels at 132, M35, G37, and V40 exhibit beta-strand secondary chemical shifts in 2-dimensional (2D) finite-pulse radiofrequency-driven recoupling NMR spectra, spatial proximities between 132 and V40 as well as between M35 and G37 in 2D dipolar-assisted rotational resonance spectra, and close proximity between M35 H-alpha and G37 H-alpha in 2D CHHC spectra. Furthermore, 2D dipolar-assisted rotational resonance analysis of an oligomer sample prepared with 30% labeled peptide indicates that the 132-V40 and M35-G37 contacts are between residues on different molecules. We employ molecular modeling to compare the newly derived experimental constraints with previously proposed geometries for arrangement of A beta molecules into oligomers. (C) 2015 Elsevier Ltd. All rights reserved.
机译：了解淀粉样β（A beta）低聚物的分子结构和潜在的组装途径将在分子水平上增进我们对阿尔茨海默氏病（AD）的理解。这种理解可能有助于疾病的预防，诊断和治疗策略，因为寡聚体在AD病理学中起着核心作用。我们最近提出了一种与固态核磁共振（NMR）分析兼容的150 kDa A beta（1-42）（A beta肽的42个残基变异体）寡聚样品的制备方法，以及我们已经证明这些低聚物和淀粉样蛋白原纤维在β链的分子间排列上不同。在这里，我们报告新的固态NMR约束条件，表明低聚物中β链的反平行分子间排列。具体而言，在132，M35，G37和V40处具有均一的C-13和N-15同位素标记的150kDa A beta（1-42）低聚物在二维（2D）有限脉冲中显示β链二级化学位移射频驱动的再耦合NMR光谱，二维双极辅助旋转共振光谱中132和V40之间以及M35和G37之间的空间邻近度，以及二维CHHC光谱中M35H-α和G37H-α之间的紧密接近。此外，用30％标记肽制备的低聚物样品的二维偶极辅助旋转共振分析表明132-V40和M35-G37接触位于不同分子上的残基之间。我们采用分子模型将新推导的实验约束与先前提出的将Aβ分子排列成低聚物的几何结构进行比较。 （C）2015 Elsevier Ltd.保留所有权利。

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