Physics department, Creighton University, Omaha, NE, USA.
Chemistry department, Creighton University, Omaha, NE, USA.
Prion. 2023 Dec;17(1):55-66. doi: 10.1080/19336896.2023.2186674.
Misfolding of the prion protein is central to prion disease aetiology. Although understanding the dynamics of the native fold helps to decipher the conformational conversion mechanism, a complete depiction of distal but coupled prion protein sites common across species is lacking. To fill this gap, we used normal mode analysis and network analysis to examine a collection of prion protein structures deposited on the protein data bank. Our study identified a core of conserved residues that sustains the connectivity across the C-terminus of the prion protein. We propose how a well-characterized pharmacological chaperone may stabilize the fold. Also, we provide insight into the effect on the native fold of initial misfolding pathways identified by others using kinetics studies.
朊病毒蛋白的错误折叠是朊病毒病发病机制的核心。尽管了解天然折叠的动力学有助于破译构象转换机制，但缺乏对种间普遍存在的远程但耦合的朊病毒蛋白位点的完整描述。为了填补这一空白，我们使用正常模式分析和网络分析来检查储存在蛋白质数据库中的一组朊病毒蛋白结构。我们的研究确定了一组保守残基，这些残基维持了朊病毒蛋白 C 端的连接性。我们提出了一种经过良好表征的药理学伴侣如何稳定这种折叠。此外，我们还深入了解了其他动力学研究确定的初始错误折叠途径对天然折叠的影响。
