NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126
NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126
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DOI：
10.1073/pnas.2433563100
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发表时间：
2003-12-09
影响因子：
11.1
通讯作者：
Roder, H
中科院分区：
文献类型：
--
作者：
Kuwata, K;Matumoto, T;Roder, H
PrP 106 -126是一种对应于人朊病毒蛋白残基107-127的肽，通过细胞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，再现朊病毒相关的传染性海绵状脑病（如牛海绵状脑病和克雅氏病）的主要神经病理学特征。尽管PrP 106 -126已显示在体外形成淀粉样原纤维，但其结构特性尚未阐明。在这里，我们调查的原纤维形成片段的小鼠朊病毒蛋白，MoPrP 106 -126，通过使用电子显微镜，CD光谱，NMR检测氢氘交换测量，分子动力学模拟的构象特征。原纤维含有约50%的β折叠结构，强酰胺交换保护仅限于跨越回文序列VAGAAAAGAV的肽的中心部分。分子动力学模拟表明，MoPrP 106 -126在水中呈现稳定的结构，由两个四链平行的β-片层组成，它们通过甲基-甲基相互作用相互紧密堆积。原纤形成涉及聚丙氨酸堆积是与实验观察一致的。
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 spongiform encephalopathies, such as bovine spongiform encephalopathy 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 conformational 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 approximate to50% beta-sheet structure, and strong amide exchange protection is limited to the central portion of the peptide spanning the palindromic sequence VAGAAAAGAV. Molecular dynamics simulations indicate that MoPrP106-126 in water assumes a stable structure consisting of two four-stranded parallel beta-sheets that are tightly packed against each other by methyl-methyl interactions. Fibril formation involving polyalanine stacking is consistent with the experimental observations.