SDSL-EPR Study of Intermediate Filament Structure

中间丝结构的SDSL-EPR研究

• 批准号: 8394915
• 负责人: PAUL Gillespie FITZGERALD
• 金额: $ 36.58万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394915
• 关键词: Behavior; Biology; Cells; Computer Simulation; Cytoskeleton; Data; Databases; Disease; Electron Spin Resonance Spectroscopy; Filament; Funding; Goals; Head; Human; Intermediate Filament Proteins; Intermediate Filaments; Keratin; Knowledge; Mechanical Stress; Mediating; Metabolic stress; Molecular Chaperones; Molecular Structure; Mutation; Pathogenesis; Pathologic; Phenotype; Phosphorylation; Physiologic pulse; Point Mutation; Process; Property; Proteins; Resolution; Site; Spin Labels; Stretching; Structure; Tail; Techniques; Technology; Time; Transmission Electron Microscopy; Vimentin; X-Ray Crystallography; base; cellular targeting; cytotoxicity; dimer; disease-causing mutation; human disease; insight; member; mutant; physical property; protein aggregation; protein misfolding; retinal rods

DESCRIPTION (provided by applicant): Intermediate Filaments (IFs) are one of three major classes of cytoskeleton found in every cell, and one of the more abundant cellular proteins. Mutations in IF proteins are responsible for at least 85 different human diseases, including many protein aggregation diseases. However, the unusual physical properties of these proteins have precluded determination of crystal structure. Because of this we have no in-depth mechanistic understanding of normal IF function, nor how mutations are pathogenic. In this proposal we will use biophysical approaches to define IF structure with a goal of elucidating IF function, and the degree to which IF structure is conserved across IF classes. This in turn will open the door to understanding pathogenesis among IF proteins, particularly those with protein aggregation phenotypes. We have assembled a team of several technologies: CW SDSL EPR, Pulsed Field SDSL EPR, Computational Modeling, High resolution TEM (Cryo- and STEM) and X Ray Crystallography.

描述（由申请人提供）：中间丝（IF）是每个细胞中发现的三大类细胞骨架之一，也是最丰富的细胞蛋白质之一。 IF 蛋白突变导致至少 85 种不同的人类疾病，包括许多蛋白质聚集疾病。然而，这些蛋白质不寻常的物理性质阻碍了晶体结构的测定。因此，我们对正常 IF 功能没有深入的机制了解，也没有突变如何致病。在本提案中，我们将使用生物物理学方法来定义 IF 结构，目的是阐明 IF 功能以及 IF 结构在 IF 类别中的保守程度。这反过来将为理解 IF 蛋白的发病机制打开大门，特别是那些具有蛋白质聚集表型的蛋白。我们组建了一支由多项技术组成的团队：CW SDSL EPR、脉冲场 SDSL EPR、计算建模、高分辨率 TEM（冷冻和 STEM）和 X 射线晶体学。