Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy.
Molecules. 2013 Sep 16;18(9):11467-84. doi: 10.3390/molecules180911467.
Many proteins perform essential biological functions by means of regions that lacking specific organized structure exist as an ensemble of interconverting transient conformers. The characterization of such regions, including the description of their structural propensities, number of conformations and relative populations can provide useful insights. Prion diseases result from the conversion of a normal glycoprotein into a misfolded pathogenic isoform. The structures of mammal and chicken prion proteins show a similar fold with a globular domain and a flexible N-terminal portion that contains different repeated regions: octarepeats (PHGGGWGQ) in mammals and hexarepeats (PHNPGY) in chickens. The higher number of prolines in the hexarepeat region suggests that this region may retain a significant amount of residual secondary structure. Here, we report the CD, NMR and MD characterization of a peptide (2-HexaPY) composed of two hexarepeats. We combine experimental NMR data and MD to investigate at atomic level its ensemble-averaged structural properties, demonstrating how each residue of both repeats has a different quantified PPII propensity that shows a periodicity along the sequence. This feature explains the absence of cooperativity to stabilize a PPII conformation. Nonetheless, such residual structure can play a role in nucleating local structural transitions as well as modulating intra-molecular or inter-molecular interactions.
许多蛋白质通过缺乏特定的组织化结构的区域来执行重要的生物学功能，这些区域作为一系列相互转化的瞬态构象存在。这些区域的特征描述，包括其结构倾向、构象数量和相对丰度的描述，可以提供有用的见解。朊病毒疾病是由正常糖蛋白转化为错误折叠的致病性异构体引起的。哺乳动物和鸡的朊病毒蛋白的结构显示出相似的折叠，具有球形结构域和柔性的 N 端部分，其中包含不同的重复区域：哺乳动物中的八重复（PHGGGWGQ）和鸡中的六重复（PHNPGY）。六重复区域中脯氨酸数量较多表明该区域可能保留了大量的残余二级结构。在这里，我们报告了由两个六重复组成的肽（2-HexaPY）的 CD、NMR 和 MD 特征。我们结合实验 NMR 数据和 MD 来研究其在原子水平上的平均结构特性，证明了每个重复的每个残基都具有不同的定量 PPII 倾向，这种倾向沿着序列呈现周期性。该特征解释了缺乏协同作用以稳定 PPII 构象的原因。尽管如此，这种残余结构可以在局部结构转变的引发中发挥作用，也可以调节分子内或分子间的相互作用。
