Polyglutamine Solution-State Structural Propensity Is Repeat Length Dependent.
Polyglutamine Solution-State Structural Propensity Is Repeat Length Dependent.
复制标题
聚谷氨酰胺溶液状态结构倾向依赖于重复长度。
DOI：
10.1021/acs.jpcb.9b01433
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Asher,SanfordA
中科院分区：
文献类型：
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作者：
Jakubek,RyanS;Workman,RileyJ;White,StephenE;Asher,SanfordA
蛋白质中的扩展聚谷氨酰胺(PolyQ)束可诱导其聚集，与许多神经退行性疾病有关。较长的多聚Q束与较快的蛋白质聚集动力学和较低的多聚Q病症状的发病年龄相关。在这里，我们使用紫外共振拉曼光谱、圆二色光谱和元动力学模拟来研究D2Q15K2(Q15)和D2Q20K2(Q20)多肽的溶液态结构。利用元动力学方法，我们探索了Q15和Q20的构象能景观，并研究了这些低能结构之间的相对能量和活化势垒。我们比较了D2Q10K2(Q10)、Q15和Q20的溶态结构，以确定多Q结构与Q道长度的关系。我们发现这些多肽可以采用两种不同的单体构象：抗聚集的PPII样构象和倾向于聚集的β链样构象。我们发现，较长的多Q多肽对易于聚集的β链状构象有更大的偏好。这种偏好可能在较长的多Q多肽聚集率增加中发挥重要作用，这被认为是导致多聚Q病患者神经退行性疾病发病年龄降低的原因。
Expanded polyglutamine (polyQ) tracts in proteins, which are known to induce their aggregation, are associated with numerous neurodegenerative diseases. Longer polyQ tracts correlate with faster protein aggregation kinetics and a decreased age of onset for polyQ disease symptoms. Here, we use UV resonance Raman spectroscopy, circular dichroism spectroscopy, and metadynamics simulations to investigate the solution-state structures of the D2Q15K2(Q15) and D2Q20K2(Q20) peptides. Using metadynamics, we explore the conformational energy landscapes of Q15 and Q20 and investigate the relative energies and activation barriers between these low-energy structures. We compare the solution-state structures of D2Q10K2(Q10), Q15, and Q20 to determine the dependence of polyQ structure on the Q tract length. We show that these peptides can adopt two distinct monomeric conformations: an aggregation-resistant PPII-like conformation and an aggregation-prone β-strand-like conformation. We find that longer polyQ peptides have an increased preference for the aggregation-prone β-strand-like conformation. This preference may play an important role in the increased aggregation rate of longer polyQ peptides that is thought to lead to decreased neurodegenerative disease age of onset for polyQ disease patients.