论文标题
人prion蛋白的天然发生变体的结构和动力学机制在防止prion转化时
Structural and Dynamical Mechanisms of a Naturally Occurring Variant of the Human Prion Protein in Preventing Prion Conversion
论文作者
论文摘要
Prion疾病与正常的螺旋细胞形式的prion蛋白（PRPC）错误折叠到富含Beta的crapie形式（PRPSC）以及随后将PRPSC聚集到淀粉样蛋白原纤维中。最近的研究表明，人类PRPC的自然发生的V127在本质上具有对prion转化和聚集的抗性，并且可以完全预防毒皮疾病。但是，基本的分子机制仍然难以捉摸。本文中，我们对人PRPC的野生型（WT）和V127变体进行多个微秒的分子动力学模拟，以在原子水平上了解V127变体的保护作用。我们的模拟表明，G127V突变不仅增加了Strand-2（S2）和Helix-2（H2）之间的S2-H2环的刚度，而且还可以增强H2 C末端区域的稳定性。有趣的是，先前的研究报告说，具有刚性S2-H2环路的动物通常不会患上病毒疾病，而H2 C末端稳定性的增加可以防止prion蛋白的错误折叠和寡聚化。使用动态网络分析确定了从G/V127到H2 C末端区域的变构路径。此外，社区网络分析表明，G127V突变增强了PRP的全球相关性和分子内相互作用，从而稳定了整体PRPC结构并抑制其转换为PRPSC。这项研究提供了对人类V127变体的机械理解，以防止prion转化，这可能有助于有效的抗腐蚀化合物的理性设计。
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.
