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Atomic-resolution dynamics on the surface of amyloid-β protofibrils probed by solution NMR

机译：溶液NMR探测β-淀粉样原纤维表面的原子分辨动力学

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摘要

Exchange dynamics between molecules free in solution and bound to the surface of a large supramolecular structure, a polymer, a membrane or solid support are important in many phenomena in biology and materials science. Here we present a novel and generally applicable solution NMR technique, known as dark-state exchange saturation transfer (DEST), to probe such exchange phenomena with atomic resolution. This is illustrated by the exchange reaction between amyloid-P (A(5) monomers and poly-disperse, NMR-invisible ('dark') protofibrils, a process of significant interest because the accumulation of toxic, aggregated forms of Ap, from small oligomers to very large assemblies, has been implicated in the aetiology of Alzheimer's disease. The ~(15)N-DEST experiment imprints with single-residue-resolution dynamic information on the protofibril-bound species in the form of ~(15)N transverse relaxation rates (~(15)N-.R_2) and exchange kinetics between monomers and protofibrils onto the easily observed two-dimensional ~1H-~(15)N correlation spectrum of the monomer. The exchanging species on the protofibril surface comprise an ensemble of sparsely populated states where each residue is either tethered to (through other residues) or in direct contact with the surface. The first eight residues exist predominantly in a mobile tethered state, whereas the largely hydrophobic central region and part of the carboxy (C)-terminal hydrophobic region are in direct contact with the protofibril surface for a significant proportion of the time. The C-terminal residues of both Aβ40 and Aβ42 display lower affinity for the protofibril surface, indicating that they are likely to be surface exposed rather than buried as in structures of Aβ fibrils~(7-10), and might therefore comprise the critical nucleus for fibril formation1112. The ~(15)N_R_2~(tethered )Viuues however, are significantly larger for the C-terminal residues of A(542 than Aβ40, which might explain the former's higher propensity for rapid aggregation and fibril formation1314.
机译：在溶液中游离并结合到大型超分子结构，聚合物，膜或固体支持物表面的分子之间的交换动力学在生物学和材料科学中的许多现象中都很重要。在这里，我们提出了一种新颖且普遍适用的溶液NMR技术，称为暗态交换饱和转移（DEST），以原子分辨率探测这种交换现象。淀粉样蛋白-P（A（5）单体与多分散，NMR不可见（“暗”）原纤维之间的交换反应可以说明这一点，这一过程引起了人们的极大兴趣，因为有毒，聚集形式的Ap的积累很小。低聚体到非常大的装配体，与阿尔茨海默氏病的病因有关。〜（15）N-DEST实验在原纤维结合的物种上以〜（15）N横向的形式在原纤维结合的物种上留下了单残留分辨率的动态信息。松弛速率（〜（15）N-.R_2）以及单体与原纤维之间的交换动力学到易于观察到的二维〜1H-〜（15）N二维相关光谱上，原纤维表面上的交换物种构成一个整体稀疏状态下，每个残基要么被束缚到（通过其他残基），要么直接与表面接触；前八个残基主要以活动的束缚态存在，而疏水性中心区域和部分羧基（C）-末端的疏水区在相当长的时间内与原纤维表面直接接触。 Aβ40和Aβ42的C末端残基对原纤维表面均显示较低的亲和力，表明它们很可能是表面暴露的而不是像Aβ纤维〜（7-10）的结构那样被掩埋，因此可能包含关键核原纤维形成11.12。然而，A（542）的C末端残基的〜（15）N_R_2〜（束缚）值明显大于Aβ40，这可能解释了前者具有更高的快速聚集和原纤维形成的倾向1314。

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  • 来源
    《Nature》 |2011年第7376期|p.268-272|共5页
  • 作者

    Nicolas L. Fawzi; Jinfa Ying; Rodolfo Ghirlando; Dennis A. Torchia; G. Marius Clore;

  • 作者单位

    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA;

    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA;

    Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA;

    National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-0520, USA;

    Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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