人朊蛋白天然突变体阻止朊蛋白转化的结构和动力学机制
Structural and Dynamical Mechanisms of a Naturally Occurring Variant of the Human Prion Protein in Preventing Prion Conversion
摘要：
朊病毒疾病与朊病毒蛋白（PrPC）的正常螺旋细胞形式错误折叠成富含β折叠的羊瘙痒病形式（PrPSc）以及随后PrPSc聚集成淀粉样原纤维有关。最近的研究表明，人PrPC的天然变异体V127对朊病毒的转化和聚集具有内在的抗性，可以完全预防朊病毒疾病。然而，潜在的分子机制仍然难以捉摸。本文中，我们对野生型（WT）和V127变体的人PrPC进行多微秒分子动力学模拟，以在原子水平上理解V127变体的保护作用。我们的模拟结果表明，G127 V突变不仅增加了链2（S2）和螺旋2（H2）之间的S2-H2环的刚性，而且变构增强了H2 C-末端区域的稳定性。有趣的是，先前的研究报道具有刚性S2-H2环的动物通常不会发生朊病毒疾病，并且H2 C-末端稳定性的增加可以防止朊病毒蛋白的错误折叠和寡聚化。利用动力学网络分析确定了G/V127到H2 C-末端区域的变构路径。此外，社区网络分析表明，G127 V突变增强了PrP的全局相关性和分子内相互作用，从而稳定了整体PrPC结构并抑制其转化为PrPSc。本研究为深入了解人V127变异体抑制朊病毒转化的机制提供了理论依据，为合理设计抗朊病毒药物提供了理论依据。
英文摘要：
Prion diseases are associated with the misfolding of the normal helical cellular form of prion protein (PrPC) into the beta-sheet-rich scrapie form (PrPSc) and the subsequent aggregation of PrPSc into amyloid fibrils. Recent studies demonstrated that a naturally occurring variant V127 of human PrPC is intrinsically resistant to prion conversion and aggregation, and can completely prevent prion diseases. However, the underlying molecular mechanism remains elusive. Herein we perform multiple microsecond molecular dynamics simulations on both wildtype (WT) and V127 variant of human PrPC to understand at atomic level the protective effect of V127 variant. Our simulations show that G127V mutation not only increases the rigidity of the S2-H2 loop between strand-2 (S2) and helix-2 (H2), but also allosterically enhances the stability of the H2 C-terminal region. Interestingly, previous studies reported that animals with rigid S2-H2 loop usually do not develop prion diseases, and the increase in H2 C-terminal stability can prevent misfolding and oligomerization of prion protein. The allosteric paths from G/V127 to H2 C-terminal region are identified using dynamical network analyses. Moreover, community network analyses illustrate that G127V mutation enhances the global correlations and intra-molecular interactions of PrP, thus stabilizing the overall PrPC structure and inhibiting its conversion into PrPSc. This study provides mechanistic understanding of human V127 variant in preventing prion conversion which may be helpful for the rational design of potent anti-prion compounds.
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