Conformational Stability of Mammalian Prion Protein Amyloid Fibrils Is Dictated by a Packing Polymorphism within the Core Region
Conformational Stability of Mammalian Prion Protein Amyloid Fibrils Is Dictated by a Packing Polymorphism within the Core Region
复制标题
DOI：
10.1074/jbc.m113.520718
复制
发表时间：
2014-01-31
影响因子：
4.8
通讯作者：
Surewicz, Witold K.
中科院分区：
文献类型：
--
作者：
Cobb, Nathan J.;Apostol, Marcin I.;Surewicz, Witold K.
背景：朊病毒株被认为是由不同构象的错误折叠朊病毒蛋白（PrP）编码的。结果如下：具有不同构象稳定性的PrP淀粉样蛋白菌株被发现具有相同的-片层核心区域，但不同的空间拉链界面。结论：PrP淀粉样蛋白稳定性的菌株特异性差异由包装多态性决定。重要性：这些发现对于理解朊病毒株的结构基础具有重要意义。哺乳动物朊病毒株被认为是由错误折叠的朊病毒蛋白PrPSc的不同构象的繁殖产生的。用于定义菌株之间差异的一个关键操作参数是PrPSc的构象稳定性，如对热和/或化学变性的抗性所定义。然而，这些稳定性差异的结构基础是未知的。为了弥合这一差距，我们已经产生了两株重组人朊病毒蛋白淀粉样原纤维，显示出显着的差异，构象稳定性，并通过一些生物物理方法，其特征在于它们。骨架酰胺氢/氘交换实验表明，在形成鲜明对比的感染性淀粉样蛋白形成的酵母朊病毒蛋白Sup 35，在-片核心大小的差异之前研究的菌株不构成哺乳动物朊病毒蛋白淀粉样蛋白菌株之间的构象稳定性的差异。相反，这些稳定性差异似乎是由淀粉样蛋白核心内不同的包装排列（即空间拉链界面）决定的，如核心区域内组氨酸侧链的不同X射线纤维衍射图和氢/氘交换动力学的大应变依赖性差异所示。尽管这项研究仅限于合成的朊病毒蛋白淀粉样纤维，但应变依赖性构象稳定性的类似结构基础可能适用于脑源性PrPSc，特别是因为尽管PrPSc的大小相似，但经常观察到PrPSc稳定性的巨大菌株特异性差异。核心区域。
Background: Prion strains are believed to be enciphered by distinct conformations of misfolded prion protein (PrP). Results: Strains of PrP amyloid with different conformational stabilities were found to have identical -sheet core regions but different steric zipper interfaces. Conclusion: Strain-specific differences in PrP amyloid stability are dictated by a packing polymorphism. Significance: These findings have implications for understanding the structural basis of prion strains.Mammalian prion strains are believed to arise from the propagation of distinct conformations of the misfolded prion protein PrPSc. One key operational parameter used to define differences between strains has been conformational stability of PrPSc as defined by resistance to thermal and/or chemical denaturation. However, the structural basis of these stability differences is unknown. To bridge this gap, we have generated two strains of recombinant human prion protein amyloid fibrils that show dramatic differences in conformational stability and have characterized them by a number of biophysical methods. Backbone amide hydrogen/deuterium exchange experiments revealed that, in sharp contrast to previously studied strains of infectious amyloid formed from the yeast prion protein Sup35, differences in -sheet core size do not underlie differences in conformational stability between strains of mammalian prion protein amyloid. Instead, these stability differences appear to be dictated by distinct packing arrangements (i.e. steric zipper interfaces) within the amyloid core, as indicated by distinct x-ray fiber diffraction patterns and large strain-dependent differences in hydrogen/deuterium exchange kinetics for histidine side chains within the core region. Although this study was limited to synthetic prion protein amyloid fibrils, a similar structural basis for strain-dependent conformational stability may apply to brain-derived PrPSc, especially because large strain-specific differences in PrPSc stability are often observed despite a similar size of the PrPSc core region.