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首页> 外文期刊>Journal of Molecular Biology >Salt-Mediated Oligomerization of the Mouse Prion Protein Monitored by Real-Time NMR
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Salt-Mediated Oligomerization of the Mouse Prion Protein Monitored by Real-Time NMR

机译：通过实时NMR监测的小鼠朊病毒蛋白的盐介导的寡聚化

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Abstract The prion protein forms β-rich soluble oligomers in vitro at pH 4 in the presence of physiological concentrations of salt. In the absence of salt, oligomerization and misfolding do not take place in an experimentally tractable timescale. While it is well established that a lowering of pH facilitates misfolding and oligomerization of this protein, the role of salt remains poorly understood. Here, solution-state NMR was used to probe perturbations in the monomeric mouse prion protein structure immediately upon salt addition, prior to the commencement of the oligomerization reaction. The weak binding of salt at multiple sites dispersed all over the monomeric protein causes a weak and non-specific perturbation of structure throughout the protein. The only significant perturbation occurs in the loop between helix 2 and 3 in and around the partially buried K193–E195 salt bridge. The disruption of this key electrostatic interaction is the earliest detectable change in the monomer before any major conformational change occurs and appears to constitute the trigger for the commencement of misfolding and oligomerization. Subsequently, the kinetics of monomer loss, due to oligomerization, was monitored at the individual residue level. The oligomerization reaction was found to be rate-limited by association and not conformational change, with an average reaction order of 2.6 across residues. Not surprisingly, salt accelerated the oligomerization kinetics, in a non-specific manner, by electrostatic screening of the highly charged monomers at acidic pH. Together, these results allowed a demarcation of the specific and non-specific effects of salt on prion protein misfolding and oligomerization. Graphical Abstract Display Omitted Highlights ? Probing the effect of salt on prion protein oligomerization by real-time NMR. ? Salt binding disrupts K193–E195 salt bridge. ? Salt aids prion protein oligomerization by electrostatic screening of charges. ? Oligomerization reaction has an average reaction order of 2.6 across residues. ? Oligomerization reaction is limited by association and not conformational change. ? Low pH oligomerization of prion protein is triggered and accelerated by salt.
机译：摘要朊病毒蛋白在盐的生理浓度存在下在pH4的体外形成富含富含的可溶性低聚物。在没有盐的情况下，在实验播种的时间内不会发生寡聚化和错误折叠。虽然很好的是，降低pH的降低促进这种蛋白质的错误折叠和低聚，但盐的作用仍然明确。这里，在脱盐反应开始之前，溶液 - 状态NMR用于立即在盐添加时立即探测单体小鼠朊病毒蛋白质结构的扰动。在分散在单体蛋白质上分散的多个位点的盐的弱结合导致整个蛋白质中的结构弱和非特异性的扰动。在部分掩埋的K193-E195盐桥中螺旋2和3之间的环中唯一显着的扰动发生在螺旋2和3之间。在发生任何主要构象变化之前，这种关键的静电相互作用的破坏是单体中最早的可检测变化，并且似乎构成了误折叠和低聚的触发。随后，在单个残基水平下监测由于寡聚化导致的单体损失动力学。发现寡聚反应是通过关联的速率限制而不是构象变化，在残留物中的平均反应顺序为2.6。毫不奇怪，盐以非特异性方式加速了低聚动力学，通过在酸性pH下静电筛选高带电荷单体的静电筛选。这些结果在一起允许盐对朊病毒蛋白质错误折叠和低聚的特异性和非特异性效果的划分。图形抽象显示省略了亮点？实时NMR探测盐对朊病毒蛋白寡聚化的影响。还是盐结合破坏K193-E195盐桥。还是盐助剂朊病毒蛋白质寡聚物通过静电筛分电荷。还是寡聚反应在残留物中的平均反应顺序为2.6。还是寡聚反应受关联的限制而不是构象变化。还是将朊病毒蛋白的低pH低聚物被抛出并通过盐加速。

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