Huntington's disease is a neurodegenerative disorder resulting from an expanded polyglutamine (polyQ) repeat of the Huntingtin (Htt) protein. Affected tissues often contain aggregates of the N-terminal Htt exon 1 (Htt-Ex1) fragment. The N-terminal N17 domain proximal to the polyQ tract is key to enhance aggregation and modulate Htt toxicity. Htt-Ex1 is intrinsically disordered, yet it has been postulated that under physiological conditions membranes induce the N17 to adopt an α-helical structure, which then plays a key role in regulating Htt protein aggregation. The present study leverages the recently available assignment of NMR peaks in an N17Q17 construct, in order to provide a look into the changes occurring in vitro upon exposing this fragment to various brain extract fragments as well as to synthetic bilayers. Residue-specific changes were observed by 3D HNCO NMR, whose nature was further clarified with ancillary CD and aggregation studies, as well as with molecular dynamic calculations. From this combination of measurements and computations, a unified picture emerges, whereby transient structures consisting of α-helices spanning a fraction of the N17 residues form during N17Q17-membrane interactions. These interactions are fairly dynamic, but they qualitatively mimic more rigid variants that have been discussed in the literature. The nature of these interactions and their potential influence on the aggregation process of these kinds of constructs under physiological conditions are briefly assessed.

中文翻译：

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在膜存在的情况下亨廷顿的N末端重排：光谱和计算的联合视角。

亨廷顿舞蹈病是一种神经退行性疾病，由亨廷顿（Htt）蛋白的扩大的聚谷氨酰胺（polyQ）重复序列引起。受影响的组织通常包含N末端Htt外显子1（Htt-Ex1）片段的聚集体。靠近polyQ通道的N端N17结构域是增强聚集和调节Htt毒性的关键。Htt-Ex1本质上是无序的，但据推测，在生理条件下，膜可诱导N17采用α螺旋结构，然后在调节Htt蛋白聚集中起关键作用。本研究利用了N17Q17构建体中最近可用的NMR峰分配，以便了解将该片段暴露于各种脑提取物片段以及合成双层后在体外发生的变化。通过3D HNCO NMR观察到残基特异性的变化，其性质通过辅助CD和聚集研究以及分子动力学计算得到了进一步阐明。从这种测量和计算的组合中，出现了一个统一的图景，由此在N17Q17膜相互作用期间形成了由跨越N17残基一部分的α螺旋组成的瞬态结构。这些相互作用是相当动态的，但是它们在质量上模仿了文献中已经讨论过的更严格的变体。简要评估了这些相互作用的性质及其在生理条件下对这类构建物聚集过程的潜在影响。从这种测量和计算的组合中，出现了一个统一的图景，由此在N17Q17膜相互作用期间形成了由跨越N17残基一部分的α螺旋组成的瞬态结构。这些相互作用是相当动态的，但是它们在质量上模仿了文献中已经讨论过的更严格的变体。简要评估了这些相互作用的性质及其在生理条件下对这类构建物聚集过程的潜在影响。从这种测量和计算的组合中，出现了一个统一的图景，由此在N17Q17膜相互作用期间形成了由跨越N17残基一部分的α螺旋组成的瞬态结构。这些相互作用是相当动态的，但是它们在质量上模仿了文献中已经讨论过的更严格的变体。简要评估了这些相互作用的性质及其在生理条件下对这类构建物聚集过程的潜在影响。但它们在质量上模仿了文献中已讨论过的更严格的变体。简要评估了这些相互作用的性质及其在生理条件下对这类构建物聚集过程的潜在影响。但它们在质量上模仿了文献中已讨论过的更严格的变体。简要评估了这些相互作用的性质及其在生理条件下对这类构建物聚集过程的潜在影响。