Structural Mechanism of Barriers to Interspecies Seeding Transmissibility of Full-Length Prion Protein Amyloid
Structural Mechanism of Barriers to Interspecies Seeding Transmissibility of Full-Length Prion Protein Amyloid
复制标题
全长朊病毒蛋白淀粉样蛋白种间传播障碍的结构机制
DOI：
10.1002/cbic.201900218
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发表时间：
2019
期刊：
影响因子：
3.2
通讯作者：
Yang Jun
中科院分区：
文献类型：
--
作者：
Ma Tao;Deng Jing;Ma Shaojie;Zhao Weijing;Chang Ziwei;Yu Kunqian;Yang Jun
朊病毒疾病的一个令人困惑的特征是跨物种障碍。这些种间屏障的详细分子机制仍然知之甚少，因为缺乏关于朊病毒蛋白（PrPSc）的羊瘙痒病亚型的高分辨率结构信息。在这项研究中，我们确定了关键作用的残基165/167的障碍播种小鼠朊蛋白（mPrP）纤维种子人类细胞朊蛋白（PrPC）。固态NMR揭示了跨越残基165-230的C末端β折叠核心和mPrP原纤维的堆积排列。残基165/167位于原纤维核心的一端。分子动力学模拟表明，接种诱导的β链结构的稳定性受到涉及残基167的侧链的氢键和涉及残基165的位阻的显著影响。这些结果表明，含有残基165/167的α2-β2环可能是种子-模板构象转换的起始位点。
A puzzling feature of prion diseases is the cross‐species barriers. The detailed molecular mechanisms underlying these interspecies barriers remain poorly understood because of a lack of high‐resolution structural information on the scrapie isoform of the prion protein (PrPSc). In this study we identified the critical role of the residues 165/167 in the barrier to seeding mouse PrP (mPrP) fibril seeds to human cellular prion protein (PrPC). Solid‐state NMR revealed a C‐terminal β‐sheet core spanning residues 165–230 and the packing arrangement of mPrP fibrils. Residues 165/167 are located on one end of the fibril core. Molecular dynamics simulations demonstrated that the stabilities of the seeding‐induced β‐strand structures are significantly impacted by hydrogen bonds involving the side chain of residue 167 and steric resistance involving residue 165. These findings suggest that the α2–β2 loop containing residues 165/167 could be the initial site of seed–template conformational conversion.