在单分子水平上观察到哺乳动物朊病毒蛋白的不同折叠机制与不同的疾病易感性

Uttam Anand, Shubhadeep Patra, Rohith Vedhthaanth Sekar, Craig R Garen, Michael T Woodside
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摘要

蛋白质 PrP 的错误折叠会导致哺乳动物朊病毒疾病。尽管 PrP 序列仅有几个氨基酸的差异,但不同物种对疾病的易感性差异很大。这些差异如何改变 PrP 的折叠和错误折叠仍不清楚。我们比较了来自狗(免疫)、仓鼠(易感)和银行田鼠(极易感性)这三种不同疾病易感性物种的单个 PrP 分子的折叠动力学。使用光学镊子进行的测量显示了这些蛋白质在折叠合作性、途径、能量障碍和动力学方面的重要差异。与仓鼠 PrP 的双态折叠不同,狗 PrP 总是通过多个中间体折叠。不过,这两种蛋白都具有快速的原生折叠、均匀的能量障碍以及不易观察到的错误折叠。银行田鼠 PrP 也通过中间体折叠,但速度更慢,而且通过非均质屏障。最值得注意的是,它从折叠状态开始形成了几种可转移的错误折叠状态。通过分析拉伸曲线中的中间产物序列,我们发现狗和银行田鼠 PrP 的折叠路径存在显著差异,这意味着序列突变改变了能量障碍,从而改变了折叠路径。这些结果表明,不同物种之间 PrP 序列的细微差别会导致折叠行为的深刻变化,从而让我们对错误折叠倾向的潜在因素有了更深入的了解。
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Different folding mechanisms in prion proteins from mammals with different disease susceptibility observed at the single-molecule level
Misfolding of the protein PrP causes prion diseases in mammals. Disease susceptibility varies widely among species, despite PrP sequences differing by only a few amino acids. How these differences alter PrP folding and misfolding remains unclear. We compared the folding dynamics of single PrP molecules from three species with different disease susceptibility: dogs (immune), hamsters (susceptible), and bank voles (extremely susceptible). Measurements with optical tweezers revealed important differences between the folding cooperativity, pathways, energy barriers, and kinetics of these proteins. In contrast to the two-state folding of hamster PrP, dog PrP always folded through multiple intermediates. However, both featured rapid native folding, homogeneous energy barriers, and no readily observable misfolding. Bank vole PrP also folded via intermediates, but more slowly and via inhomogeneous barriers. Most notably, it formed several metastable misfolded states starting from the unfolded state. Analyzing the sequence of intermediates seen in pulling curves, we found significant differences in the folding pathways for dog and bank vole PrP, implying that sequence mutations altered energy barriers so as to redirect folding pathways. These results show that subtle differences in PrP sequence between species produce profound changes in folding behavior, providing insight into the factors underlying misfolding propensity.
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