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首页> 外文期刊>Journal of Molecular Biology >Gly25-Ser26 amyloid β-protein structural isomorphs produce distinct Aβ42 conformational dynamics and assembly characteristics
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Gly25-Ser26 amyloid β-protein structural isomorphs produce distinct Aβ42 conformational dynamics and assembly characteristics

机译：GLY25-SER26淀粉样蛋白β-蛋白质结构异构体产生明显的Aβ42构象动态和组装特性

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摘要

One of the earliest events in amyloid β-protein (Aβ) self-Association is nucleation of Aβ monomer folding through formation of a turn at Gly25-Lys28. We report here the effects of structural changes at the center of the turn, Gly25-Ser26, on Aβ42 conformational dynamics and assembly. We used "click peptide" chemistry to quasi-synchronously create Aβ42 from 26-O-Acyliso-Aβ42 (iAβ42) through a pH jump from 3 to 7.4. We also synthesized Nα-Acetyl-Ser26-iAβ42 (Ac-iAβ42), which cannot undergo O → N acyl chemistry, to study the behavior of this ester form of Aβ42 itself at neutral pH. Data from experiments monitoring increases in β-sheet formation (thioflavin T, CD), hydrodynamic radius (RH), scattering intensity (quasielastic light scattering spectroscopy), and extent of oligomerization (ion mobility spectroscopy-mass spectrometry) were quite consistent. A rank order of Ac-iAβ42 iAβ42 Aβ42 was observed. Photochemically cross-linked iAβ42 displayed an oligomer distribution with a prominent dimer band that was not present with Aβ42. These dimers also were observed selectively in iAβ42 in ion mobility spectrometry experiments. The distinct biophysical behaviors of iAβ42 and Aβ42 appear to be due to the conversion of iAβ42 into "pure" Aβ42 monomer, a nascent form of Aβ42 that does not comprise the variety of oligomeric and aggregated states present in pre-existent Aβ42. These results emphasize the importance of the Gly25-Ser26 dipeptide in organizing Aβ42 monomer structure and thus suggest that drugs altering the interactions of this dipeptide with neighboring side-chain atoms or with the peptide backbone could be useful in therapeutic strategies targeting formation of Aβ oligomers and higher-order assemblies.
机译：淀粉样蛋白β-蛋白（Aβ）自我关联中最早的事件之一是通过在Gly25-Lys28的匝数形成Aβ单体折叠的核心。我们在此报告结构变化在转弯中心的影响GLY25-SER26在Aβ42构象动态和组装中。我们使用“点击肽”化学来通过pH从3至7.4跳至向准从26-O-酰基血清-Aβ42（IAβ42）中的Aβ42。我们还合成了Nα-乙酰基-Ser26-IAβ42（AC-IAβ42），其不能经历O→N酰基化学，研究Aβ42本身在中性pH下的该酯形式的行为。来自实验监测的数据在β-片状形成（硫蛋白T，Cd），流体动力半径（RH），散射强度（准弹性光散射光谱）和低聚（离子迁移谱 - 质谱）的程度相当一致。 AC-IAβ42＆gt的等级顺序。 IAβ42＆观察到Aβ42。光化学上交联的IAβ42显示了利用Aβ42不存在的突出二聚体带的低聚物分布。在离子迁移光谱实验中，在IAβ42中选择性地观察到这些二聚体。 IAβ42和Aβ42的不同的生物物理行为似乎是由于IAβ42转化为“纯”Aβ42单体，一种新的Aβ42形式，其不包含在预先存在的Aβ42中存在的各种低聚和聚集状态。这些结果强调Gly25-Ser26二肽在组织Aβ42单体结构中的重要性，从而表明药物改变与相邻的侧链原子或肽骨架的这种二肽的相互作用可用于靶向Aβ低聚物的形成的治疗策略中高阶装配。

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  • 来源
    《Journal of Molecular Biology》 |2014年第13期|共20页
  • 作者

    RoychaudhuriR.; LomakinA.; BernsteinS.; ZhengX.; CondronM.M.; BenedekG.B.; BowersM.; TeplowD.B.;

  • 作者单位

    Department of Neurology David Geffen School of Medicine University of California Los Angeles 635;

    Department of Physics and Center for Materials Science and Engineering Massachusetts Institute of;

    Department of Chemistry and Biochemistry University of California Santa Barbara Santa Barbara CA;

    Department of Chemistry and Biochemistry University of California Santa Barbara Santa Barbara CA;

    Department of Neurology David Geffen School of Medicine University of California Los Angeles 635;

    Department of Physics and Center for Materials Science and Engineering Massachusetts Institute of;

    Department of Chemistry and Biochemistry University of California Santa Barbara Santa Barbara CA;

    Department of Neurology David Geffen School of Medicine University of California Los Angeles 635;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子生物学;
  • 关键词

    Alzheimer's disease; amyloid β-protein; fibril formation; ion mobility spectroscopy-mass spectrometry; oligomerization;

    机译：阿尔茨海默病;淀粉样蛋白β-蛋白质;原纤维形成;离子迁移谱 - 质谱;寡聚化;

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