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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126
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NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126

机译：NMR检测到的氢交换和分子动力学模拟可提供结构信息，了解protein病毒蛋白片段106-126的原纤维形成

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摘要

PrP106-126, a peptide corresponding to residues 107-127 of the human prion protein, induces neuronal cell death by apoptosis and causes proliferation and hypertrophy of glia, reproducing the main neuropathological features of prion-related transmissible spongi-form encephalopathies, such as bovine spongiform encephalopa-thy and Creutzfeldt-Jakob disease. Although PrP106-126 has been shown to form amyloid-like fibrils in vitro, their structural properties have not been elucidated. Here, we investigate the confor-mational characteristics of a fibril-forming fragment of the mouse prion protein, MoPrP106-126, by using electron microscopy, CD spectroscopy, NMR-detected hydrogen-deuterium exchange measurements, and molecular dynamics simulations. The fibrils contain ≈50% β-sheet structure, and strong amide exchange protection is limited to the central portion of the peptide spanning the palin-dromic sequence VAGAAAAGAV. Molecular dynamics simulations indicate that MoPrP106-126 in water assumes a stable structure consisting of two four-stranded parallel β-sheets that are tightly packed against each other by methyl-methyl interactions. Fibril formation involving polyalanine stacking is consistent with the experimental observations.
机译：PrP106-126，一种对应于人类病毒蛋白残基107-127的肽，可通过凋亡诱导神经元细胞死亡，并引起神经胶质细胞增殖和肥大，重现病毒相关的可传播海绵状脑病（如牛）的主要神经病理学特征海绵状脑病和克雅氏病。尽管已显示PrP106-126在体外形成淀粉样样原纤维，但尚未阐明其结构性质。在这里，我们通过使用电子显微镜，CD光谱，NMR检测的氢-氘交换测量和分子动力学模拟，研究了小鼠病毒蛋白MoPrP106-126的原纤维形成片段的构象特征。原纤维具有约50％的β-折叠结构，强酰胺交换保护作用仅限于跨越花粉序列VAGAAAAGAV的肽的中心部分。分子动力学模拟表明，水中的MoPrP106-126具有稳定的结构，该结构由两个四链平行的β-折叠构成，它们通过甲基-甲基相互作用彼此紧密地堆积在一起。涉及聚丙氨酸堆积的原纤维形成与实验观察结果一致。

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