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

构象异质性和 α-片层：Abeta 变体毒性的决定因素

基本信息

批准号：
9975338
负责人：
VALERIE D DAGGETT
金额：
$ 74.15万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9975338
关键词：
Adopted Affect Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloid beta-Protein Amyloidosis Animal Model Behavior Binding Biological Biological Assay Biological Models Cell model Cells Cerebrospinal Fluid Circular Dichroism Electrophoresis Electrophysiology (science)Event Heterogeneity Human Immobilization In Vitro Libraries Light Liquid substance Maps Measurement Methodology Methods Microfluidics Modeling Molecular Conformation Molecular Sieve Chromatography Molecular Weight Monitor Mus Nature Patients Peptide Conformation Peptides Preparation Process Property Proteins Reagent Role Sampling Site Spectrum Analysis Standardization Stretching Structure System Technology Toxic effect Variant Vertebral column Work amyloid formation amyloid peptide amyloid structure amyloidogenesis base conformer cytotoxicity data warehouse design experimental study in vivo inhibitor/antagonist molecular dynamics monomer mutant neuroblastoma cell neuroinflammation novel novel strategies simulation

项目摘要

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.

淀粉样蛋白疾病涉及会议变化和正常固体胡椒粉和蛋白质的聚集。随着这些蛋白质的变化开始错误折叠和汇总，它们通过了有毒的固体寡聚阶段和然后它们最终形成不溶性的原纤维。我们花了很多年来表征这一点的早期事件进展，并观察到多种淀粉样蛋白相关的肽和蛋白质尽管主要和三级结构明显，但蛋白质。我们“发现”的结构，我们称为α-片，虽然在正常蛋白质中很少见，但已经在实验中观察到，并且在蛋白质数据库。我们开始了一项努力，以完整的结构（以及α-片）以及它们抑制这些系统中淀粉样蛋白形成的能力来设计和评估小宠物。这些从头设计的Petides抑制了多个无关淀粉样蛋白系统的聚集，表明我们是针对通用结构的。固定时，这些设计还选择性地结合了这些淀粉样蛋白在单体或原纤维上的有毒寡聚形式。在这里，我们建议通过研究与阿尔茨海默氏病相关的ABETA变体的淀粉样蛋白发生期间的α-单层形式。然后，将在体外，神经母细胞瘤细胞以及不同生物学相关的系统中评估使用从头α-表设计靶向有毒的低聚物的影响。