Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, Alberta, Canada T6G 2M8; Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
J Mol Biol. 2019 Jun 28;431(14):2599-2611. doi: 10.1016/j.jmb.2019.04.027. Epub 2019 Apr 26.
Prion diseases are neurodegenerative disorders caused by the misfolding of the cellular prion protein (PrP). Gerstmann-Sträussler-Scheinker syndrome is an inherited prion disease with one early-onset allele (HRdup) containing an eight-amino-acid insertion; this LGGLGGYV insert is positioned after valine 129 (human PrP sequence) in a hydrophobic tract in the natively disordered region. Here we have characterized the structure and explored the molecular motions and dynamics of HRdup PrP and a control allele. High-resolution NMR data suggest that the core of HRdup has a canonical PrP structure, yet a nascent β-structure is observed in the flexible elongated hydrophobic region of HRdup. In addition, using mouse PrP sequence, we observed that a methionine/valine polymorphism at codon 128 (equivalent of methionine/valine 129 in human sequence) and oligomerization caused by high protein concentration affects conformational exchange dynamics at residue G130. We hypothesize that with the β-structure at the N-terminus, the hydrophobic region of HRdup can adopt a fully extended configuration and fold back to form an extended β-sheet with the existing β-sheet. We propose that these structures are early chemical events in disease pathogenesis.
朊病毒病是由细胞朊蛋白（PrP）错误折叠引起的神经退行性疾病。格斯特曼-施特劳斯勒-谢因克综合征是一种遗传性朊病毒病，有一种早发型等位基因（HRdup）含有一个八氨基酸插入；该 LGGLGGYV 插入位于第 129 位缬氨酸（人 PrP 序列）之后，在天然无序区的疏水区段。在这里，我们对 HRdup PrP 和对照等位基因的结构进行了表征，并探索了其分子运动和动力学。高分辨率 NMR 数据表明，HRdup 的核心具有典型的 PrP 结构，但在 HRdup 柔性伸长疏水区段观察到初生β结构。此外，使用小鼠 PrP 序列，我们观察到 128 位密码子的蛋氨酸/缬氨酸多态性（与人序列中第 129 位蛋氨酸/缬氨酸等效）和高蛋白质浓度引起的寡聚化会影响 G130 残基的构象交换动力学。我们假设，由于 N 端的β结构，HRdup 的疏水区段可以采用完全伸展的构型，并折叠回与现有β-折叠形成扩展的β-折叠。我们提出这些结构是疾病发病机制中的早期化学事件。
