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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β蛋白结构同构物产生独特的Aβ42构象动力学和组装特征

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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β-蛋白（Aβ）自缔合的最早事件之一是通过在Gly25-Lys28处形成转弯来折叠Aβ单体的核。我们在此报告转弯中心Gly25-Ser26的结构变化对Aβ42构象动力学和组装的影响。我们使用“点击肽”化学方法，通过从3跃升至7.4的pH值，从26-O-酰基异Aβ42（iAβ42）准同步生成Aβ42。我们还合成了Nα-乙酰基-Ser26-iAβ42（Ac-iAβ42），它不能进行O→N酰基化学反应，以研究这种酯形式的Aβ42本身在中性pH下的行为。来自监测β-片层形成（硫黄素T，CD），流体动力学半径（RH），散射强度（准弹性光散射光谱）和低聚程度（离子迁移光谱-质谱）增加的实验数据非常一致。观察到Ac-iAβ42>iAβ42>Aβ42的等级顺序。光化学交联的iAβ42表现出具有突出的二聚体带的低聚物分布，而Aβ42则不存在。这些二聚体还在离子迁移谱实验中的iAβ42中选择性观察到。 iAβ42和Aβ42的独特生物物理行为似乎是由于iAβ42转化为“纯”Aβ42单体而引起的，这是Aβ42的新生形式，其不包含先前存在的Aβ42中存在的多种寡聚和聚集态。这些结果强调了Gly25-Ser26二肽在组织Aβ42单体结构中的重要性，因此表明，改变该二肽与相邻侧链原子或与肽主链的相互作用的药物可用于靶向Aβ寡聚体形成的治疗策略。高阶程序集。

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