Ronga Luisa, Tizzano Barbara, Palladino Pasquale, Ragone Raffaele, Urso Emanuela, Maffia Michele, Ruvo Menotti, Benedetti Ettore, Rossi Filomena
Dipartimento delle Scienze Biologiche, C I R Pe B, Università Federico II di Napoli and Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Napoli, Italy.
Chem Biol Drug Des. 2006 Sep;68(3):139-47. doi: 10.1111/j.1747-0285.2006.00427.x.
Prion diseases are characterized by the conversion of the physiological cellular form of the prion protein (PrP(C)) into an insoluble, partially protease-resistant abnormal scrapie form (PrP(Sc)). PrP(C) is normally expressed in mammalian cell and is highly conserved among species, although its role in cellular function remains elusive. The conversion of PrP(C) to PrP(Sc) parallels a conformational change of the polypeptide from a predominantly alpha-helical to a highly beta-sheet secondary structure. The pathogenesis and molecular basis of the consequent nerve cell loss are not understood. Limited structural information is available on aggregate formation by this protein as the possible cause of these diseases and on its toxicity. This brief overview focuses on the large amount of structure-activity studies based on the prion fragment approach, hinging on peptides derived from the unstructured N-terminal and globular C-terminal domains. It is well documented that most of the fragments with regular secondary structure, with the exception of helices 1 and 3, possess a high beta-sheet propensity and tendency to form beta-sheet-like aggregates. In this context, helix 2 plays a crucial role because it is able to adopt both misfolded and partially helical conformation. However, only a few mutants are able to display its intrinsic neurotoxicity.
朊病毒疾病的特征是朊病毒蛋白的生理细胞形式（PrP(C)）转变为不溶性、部分抗蛋白酶的异常瘙痒病形式（PrP(Sc)）。PrP(C)通常在哺乳动物细胞中表达，并且在物种间高度保守，尽管其在细胞功能中的作用仍不清楚。PrP(C)向PrP(Sc)的转变伴随着多肽从主要的α-螺旋二级结构向高度β-折叠二级结构的构象变化。随后神经细胞损失的发病机制和分子基础尚不清楚。关于这种蛋白质聚集形成作为这些疾病可能原因及其毒性的结构信息有限。本简要概述重点关注基于朊病毒片段方法的大量结构活性研究，这些研究依赖于源自无结构N端和球状C端结构域的肽。有充分记录表明，除螺旋1和3外，大多数具有规则二级结构的片段具有高β-折叠倾向和形成β-折叠样聚集体的趋势。在这种情况下，螺旋2起着关键作用，因为它能够呈现错误折叠和部分螺旋构象。然而，只有少数突变体能够表现出其内在的神经毒性。
