Aggregation of otherwise soluble proteins into amyloid structures is a hallmark of many disorders, such as Alzheimer's and Parkinson's disease. There is an increasing evidence that the small aggregations, instead of ordered fibrillar aggregates, are the main structures causing toxicity. However, the studies on the small aggregation phase are limited due to the variety of structures and the complexity of the physiological environment. Here, we showed an engineered co-assembling oppositely charged amyloid-like peptide pair ([II]) as a simple tool to establish methodologies to study the mechanism and kinetics of aggregation and relate its aggregation to toxicity. The toxicity mechanism of [II] is through cell membrane damage and stress, shown with YAP and eIF2α, as in the amyloid protein-initiated diseases. Albumin is demonstrated as an extrinsic and physiologically relevant molecule in controlling the aggregation lag time and toxicity of [II]. This study represents a molecular engineering strategy to create simplistic molecular tools for establishing methodologies to study the aggregation process and kinetics of amyloid-like proteins in various conditions. Understanding the nature of protein aggregation kinetics and linking them to their biological functions through engineered peptides paves the way for future designs and drug development applications.

中文翻译：

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通过可调节肽与白蛋白的聚集来控制膜损伤


可溶性蛋白质聚集成淀粉样蛋白结构是许多疾病的标志，例如阿尔茨海默病和帕金森病。越来越多的证据表明，小聚集体而不是有序的纤维聚集体是引起毒性的主要结构。然而，由于结构的多样性和生理环境的复杂性，对小聚集相的研究受到限制。在这里，我们展示了一种工程共组装的带相反电荷的淀粉样蛋白样肽对（[II]），作为一种简单的工具来建立研究聚集机制和动力学的方法，并将其聚集与毒性联系起来。 [II] 的毒性机制是通过细胞膜损伤和应激，如 YAP 和 eIF2α 所示，如在淀粉样蛋白引发的疾病中一样。白蛋白被证明是一种外在的生理相关分子，可控制 [II] 的聚集滞后时间和毒性。这项研究代表了一种分子工程策略，旨在创建简单的分子工具，以建立研究淀粉样蛋白在各种条件下的聚集过程和动力学的方法。了解蛋白质聚集动力学的本质并通过工程肽将其与其生物功能联系起来，为未来的设计和药物开发应用铺平了道路。