Evidence for assembly of prions with left-handed β3-helices into trimers
Evidence for assembly of prions with left-handed β3-helices into trimers
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DOI：
10.1073/pnas.0402254101
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发表时间：
2004-06-01
影响因子：
11.1
通讯作者：
Cohen, FE
中科院分区：
文献类型：
--
作者：
Govaerts, C;Wille, H;Cohen, FE
使用低分辨率纤维衍射，电子显微镜和原子力显微镜对各种淀粉样蛋白原纤维的研究表明，错误折叠的构象必须是模块化的，紧凑的，并采用交叉β结构。在早期的研究中，我们使用电子晶体学描绘了朊病毒蛋白N端截短的致病同种型（PrPsc）的分子模型，命名为PrP 27-30，它聚合成淀粉样纤维，但我们无法选择右手或左手β螺旋模型的三聚体或六聚体排列。从119个在球状蛋白中观察到的全β折叠的研究中，我们现在已经确定，如果PrPsc遵循已知的蛋白质折叠，则它采用β-三明治或平行β-螺旋结构。随着越来越多的证据表明淀粉样蛋白中存在平行的β-折叠组织，我们认为PrP的序列与平行的左手β-螺旋折叠是相容的。左手β-螺旋很容易形成三聚体，为PrPsc的三聚体模型提供了天然模板。该三聚体模型将来自残基89-175的PrP序列与C末端（残基176-227）以β-螺旋构象容纳，保留在正常细胞同种型中观察到的二硫键连接的α-螺旋构象。此外，所提出的模型匹配的PrP 27-30晶体的结构限制，定位残基141-176和N-连接的糖适当。我们的平行左手β-螺旋模型提供了一个连贯的框架，是一致的许多结构，生化，免疫学和传播功能的朊病毒。此外，PrPsc的平行左手β-螺旋模型可能为其他一些神经退行性疾病中发现的细丝结构提供重要线索。
Studies using low-resolution fiber diffraction, electron microscopy, and atomic force microscopy on various amyloid fibrils indicate that the misfolded conformers must be modular, compact, and adopt a cross-beta structure. In an earlier study, we used electron crystallography to delineate molecular models of the N-terminally truncated, disease-causing isoform (PrPsc) of the prion protein, designated PrP 27-30, which polymerizes into amyloid fibrils, but we were unable to choose between a trimeric or hexameric arrangement of right- or left-handed beta-helical models. From a study of 119 all-beta folds observed in globular proteins, we have now determined that, if PrPsc follows a known protein fold, it adopts either a beta-sandwich or parallel beta-helical architecture. With increasing evidence arguing for a parallel beta-sheet organization in amyloids, we contend that the sequence of PrP is compatible with a parallel left-handed beta-helical fold. Left-handed beta-helices readily form trimers, providing a natural template for a trimeric model of PrPsc. This trimeric model accommodates the PrP sequence from residues 89-175 in a beta-helical conformation with the C terminus (residues 176-227), retaining the disulfide-linked a-helical conformation observed in the normal cellular isoform. In addition, the proposed model matches the structural constraints of the PrP 27-30 crystals, positioning residues 141-176 and the N-linked sugars appropriately. Our parallel left-handed beta-helical model provides a coherent framework that is consistent with many structural, biochemical, immunological, and propagation features of prions. Moreover, the parallel left-handed beta-helical model for PrPsc may provide important clues to the structure of filaments found in some other neurodegenerative diseases.