Differential stability of the bovine prion protein upon urea unfolding
Differential stability of the bovine prion protein upon urea unfolding
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DOI：
10.1002/pro.231
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发表时间：
2009-10-01
期刊：
影响因子：
8
通讯作者：
Sykes, Brian D.
中科院分区：
文献类型：
--
作者：
Julien, Olivier;Chatterjee, Subhrangsu;Sykes, Brian D.
Prion病，或称传染性海绵状脑病，是一组与中枢神经系统内源性蛋白(PrP)结构转换相关的感染性神经疾病。这种蛋白有两种主要形式：天然的非感染性细胞形式PrPC和错误折叠的、具有感染性和抗蛋白酶K的形式PrPSc。PrPC的C-末端结构域主要是α-螺旋结构，而PrPSc已知聚集成一组β-折叠，形成淀粉样纤维。为了确定PrPC在转化为感染性构象的初始步骤中可能涉及的区域，我们使用高分辨率核磁共振谱表征了牛重组PrPC(残基121到230)在与变性尿素展开过程中的稳定性和结构。对800 MHz H-1核磁共振谱的分析揭示了有关展开时发生的结构变化的地区特有信息。我们的数据表明，PrPC天然β-折叠的解离是尿素诱导的去折叠过程中的主要步骤，而螺旋之间强烈的疏水相互作用，即使在非常高的尿素浓度下，也能稳定这些区域。
Prion diseases, or transmissible spongiform encephalopathies, are a group of infectious neurological diseases associated with the structural conversion of an endogenous protein (PrP) in the central nervous system. There are two major forms of this protein: the native and noninfectious cellular form, PrPC; and the misfolded, infectious, and proteinase K-resistant form, PrPSc. The C-terminal domain of PrPC is mainly alpha-helical in structure, whereas PrPSc in known to aggregate into an assembly of beta-sheets, forming amyloid fibrils. To identify the regions of PrPC potentially involved in the initial steps of the conversion to the infectious conformation, we have used high-resolution NMR spectroscopy to characterize the stability and structure of bovine recombinant PrPC (residues 121 to 230) during unfolding with the denaturant urea. Analysis of the 800 MHz H-1 NMR spectra reveals region-specific information about the structural changes occurring upon unfolding. Our data suggest that the dissociation of the native beta-sheet of PrPC is a primary step in the urea-induced unfolding process, while strong hydrophobic interactions between helices alpha 1 and alpha 3, and between alpha 2 and alpha 3, stabilize these regions even at very high concentrations of urea.