Conformational heterogeneity and alpha-sheet: Determinants of toxicity in Abeta variants

淀粉样蛋白疾病涉及正常可溶性多肽和蛋白质的构象变化和聚集。 随着这些蛋白质的变化，它们开始错误折叠和聚集，经过有毒的可溶性低聚物阶段，并 然后，它们最终形成不溶于水的纤维。我们花了很多年来描述这一早期事件的特征 进展，并观察到多种淀粉样蛋白相关多肽和 蛋白质，尽管一级结构和三级结构截然不同。我们“发现”的结构，我们称之为α-Sheet， 虽然在正常蛋白质中很少见，但已经在实验中观察到，α-链的短延伸存在于 蛋白质数据库。我们开始努力设计和评估具有互补结构的小肽，也就是α-Sheet，以及它们在这些系统中抑制淀粉样蛋白形成的能力。这些从头设计的多肽抑制多个不相关的淀粉样蛋白系统的聚集，表明我们的目标是一种类属结构。当固定化时，这些设计还选择性地将这些淀粉样蛋白的有毒寡聚形式结合在单体或纤维上。在这里，我们建议通过调查与阿尔茨海默病相关的Aβ变异体在淀粉样蛋白形成过程中是否形成α-Sheet来扩展这些研究。然后，将在体外、神经母细胞瘤细胞和不同的、更具生物学意义的系统中评估通过从头开始的α-Sheet设计来靶向有毒低聚物的效果。

Amyloid diseases involve conformational changes and aggregation of normally soluble peptides and proteins. As these proteins change begin to misfold and aggregate they pass through a toxic soluble oligomer stage and then they ultimately form insoluble fibrils. We have spent many years characterizing the early events in this progression, and have observed a common structure form among multiple amyloid-associated peptides and proteins despite distinct primary and tertiary structure. The structure we “discovered”, which we call α-sheet, while rare in normal proteins, has been observed experimentally, and short stretches of α-strand are present in the Protein Data Bank. We embarked on an endeavor to design and evaluate small peptides with complementary structures, also α-sheets, and their ability to inhibit amyloid formation in these systems. These de novo designed peptides inhibit the aggregation of multiple unrelated amyloid systems, indicating that we are targeting a generic structure. When immobilized, these designs also selectively bind the toxic oligomeric forms of these amyloid proteins over the monomers or fibrils. Here we propose to extend these studies by investigating whether α-sheet forms during amyloidogenesis of Abeta variants associated with Alzheimer's disease. The effects of targeting the toxic oligomers with de novo α-sheet designs will then be evaluated in vitro, in neuroblastoma cells, and in different, more biologically relevant systems.