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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Elongated oligomers in β_2-microglobulin amyloid assembly revealed by ion mobility spectrometry-mass spectrometry
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Elongated oligomers in β_2-microglobulin amyloid assembly revealed by ion mobility spectrometry-mass spectrometry

机译：离子淌度质谱-质谱法揭示β_2-微球蛋白淀粉样蛋白组装中的伸长寡聚体

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摘要

The key to understanding amyloid disease is the characterization of oligomeric species formed during the early stages of fibril assembly. Here we have used electrospray ionisation-ion mobility spectrometry-mass spectrometry to identify and structurally characterize the oligomers formed during amyloid assembly from β_2-microglobulin (β_2m). β_2m oligomers are shown to have collision cross-sections consistent with monomeric units arranged in elongated assemblies prior to fibril formation. Direct observation, separation, and quantification of transient oligomeric species reveals that monomers to tetramers are populated through the lag phase with no evidence for the significant population of larger oligomeric species under the conditions employed. The dynamics of each oligomeric species were monitored directly within the ensemble at concentrations commensurate with amyloid formation by observing the subunit exchange of ~(14)N- and ~(15)N- labeled oligomers. Analysis of the data revealed a decrease in oligomer dynamics concomitant with increasing oligomer size and the copopulation of dynamic dimeric and trimeric species with more stable trimeric and tetrameric species. The results presented map the events occurring during the lag phase of fibril formation and give a clear insight into the structural characteristics and dynamic nature of the β_2m oligomers, demonstrating the existence of elongated assemblies arising from an intact amyloidogenic protein during fibril formation.
机译：理解淀粉样蛋白疾病的关键是在原纤维组装的早期阶段形成的寡聚体的表征。在这里，我们已经使用电喷雾电离-离子迁移谱-质谱法来鉴定和结构化由β_2-微球蛋白（β_2m）形成淀粉样蛋白过程中形成的低聚物。 β_2m低聚物的碰撞截面与原纤维形成之前排列成细长组件的单体单元一致。对瞬时低聚物种的直接观察，分离和定量分析表明，单体至四聚体通过滞后相被填充，没有证据表明在所采用的条件下存在较大数量的较大的低聚物种。通过观察〜（14）N-和〜（15）N-标记的寡聚体的亚基交换，在集合体中以与淀粉样蛋白形成相当的浓度直接监测每个寡聚体的动力学。数据分析显示，随着低聚物尺寸的增加以及动态二聚体和三聚体物种与更稳定的三聚体和四聚体物种的共存，低聚物动力学降低。给出的结果绘制了原纤维形成滞后阶段发生的事件的图，并清楚地了解了β_2m低聚物的结构特征和动力学性质，证明了原纤维形成过程中完整的淀粉样蛋白产生的细长组装体的存在。

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    David P. Smith; Sheena E. Radford; Alison E. Ashcr;

  • 作者单位

    Astbury Centre for Structural Molecular Biology, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom;

    Astbury Centre for Structural Molecular Biology, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom;

    Astbury Centre for Structural Molecular Biology, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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