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The Kinetics of Amyloid Fibrillar Aggregation of Uperin 3.5 Is Directed by the Peptide's Secondary Structure.
Biochemistry ( IF 2.9 ) Pub Date : 2019-08-06 00:00:00 , DOI: 10.1021/acs.biochem.9b00536 Torsten John 1, 2, 3 , Tiara J A Dealey 1 , Nicholas P Gray 1 , Nitin A Patil 4 , Mohammed A Hossain 4 , Bernd Abel 2, 3 , John A Carver 5 , Yuning Hong 6 , Lisandra L Martin 1
Biochemistry ( IF 2.9 ) Pub Date : 2019-08-06 00:00:00 , DOI: 10.1021/acs.biochem.9b00536 Torsten John 1, 2, 3 , Tiara J A Dealey 1 , Nicholas P Gray 1 , Nitin A Patil 4 , Mohammed A Hossain 4 , Bernd Abel 2, 3 , John A Carver 5 , Yuning Hong 6 , Lisandra L Martin 1
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Many peptides aggregate into insoluble β-sheet rich amyloid fibrils. Some of these aggregation processes are linked to age-related diseases, such as Alzheimer’s disease and type 2 diabetes. Here, we show that the secondary structure of the peptide uperin 3.5 directs the kinetics and mechanism of amyloid fibrillar aggregation. Uperin 3.5 variants were investigated using thioflavin T fluorescence assays, circular dichroism spectroscopy, and structure prediction methods. Our results suggest that those peptide variants with a strong propensity to form an α-helical secondary structure under physiological conditions are more likely to aggregate into amyloid fibrils than peptides in an unstructured or “random coil” conformation. This conclusion is in good agreement with the hypothesis that an α-helical transition state is required for peptide aggregation into amyloid fibrils. Specifically, uperin 3.5 variants in which charged amino acids were replaced by alanine were richer in α-helical content, leading to enhanced aggregation compared to that of wild type uperin 3.5. However, the addition of 2,2,2-trifluoroethanol as a major co-solute or membrane-mimicking phospholipid environments locked uperin 3.5 to the α-helical conformation preventing amyloid aggregation. Strategies for stabilizing peptides into their α-helical conformation could provide therapeutic approaches for overcoming peptide aggregation-related diseases. The impact of the physiological environment on peptide secondary structure could explain aggregation processes in a cellular environment.
中文翻译：
Uperin 3.5的淀粉样原纤维聚集动力学由肽的二级结构指导。
许多肽聚集成不溶的富含β-折叠的淀粉样蛋白原纤维。这些聚集过程中的一些与与年龄相关的疾病有关，例如阿尔茨海默氏病和2型糖尿病。在这里，我们表明，肽uperin 3.5的二级结构指导淀粉样蛋白原纤维聚集的动力学和机理。使用硫黄素T荧光测定，圆二色光谱和结构预测方法研究了Uperin 3.5变体。我们的结果表明，与那些具有非结构或“无规卷曲”构象的肽相比，在生理条件下具有很强的形成α-螺旋二级结构倾向的那些肽变体更可能聚集成淀粉样原纤维。该结论与以下假设非常吻合：肽聚集为淀粉样蛋白原纤维需要α-螺旋过渡态。具体地，其中带电荷的氨基酸被丙氨酸替代的uperin 3.5变体的α-螺旋含量更丰富，与野生型uperin 3.5相比，导致增强的聚集。但是，添加2,2,2-三氟乙醇作为主要的共溶质或类似膜的磷脂环境，可将uperin 3.5锁定在α-螺旋构象上，从而防止淀粉样蛋白聚集。将肽稳定为其α-螺旋构象的策略可以为克服与肽聚集相关的疾病提供治疗方法。生理环境对肽二级结构的影响可以解释细胞环境中的聚集过程。
更新日期：2019-08-06
中文翻译：
Uperin 3.5的淀粉样原纤维聚集动力学由肽的二级结构指导。
许多肽聚集成不溶的富含β-折叠的淀粉样蛋白原纤维。这些聚集过程中的一些与与年龄相关的疾病有关，例如阿尔茨海默氏病和2型糖尿病。在这里，我们表明，肽uperin 3.5的二级结构指导淀粉样蛋白原纤维聚集的动力学和机理。使用硫黄素T荧光测定，圆二色光谱和结构预测方法研究了Uperin 3.5变体。我们的结果表明，与那些具有非结构或“无规卷曲”构象的肽相比，在生理条件下具有很强的形成α-螺旋二级结构倾向的那些肽变体更可能聚集成淀粉样原纤维。该结论与以下假设非常吻合：肽聚集为淀粉样蛋白原纤维需要α-螺旋过渡态。具体地，其中带电荷的氨基酸被丙氨酸替代的uperin 3.5变体的α-螺旋含量更丰富，与野生型uperin 3.5相比，导致增强的聚集。但是，添加2,2,2-三氟乙醇作为主要的共溶质或类似膜的磷脂环境，可将uperin 3.5锁定在α-螺旋构象上，从而防止淀粉样蛋白聚集。将肽稳定为其α-螺旋构象的策略可以为克服与肽聚集相关的疾病提供治疗方法。生理环境对肽二级结构的影响可以解释细胞环境中的聚集过程。
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