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SDSL-EPR STUDY OF INTERMEDIATE FILAMENT STRUCTURE

中间丝结构的 SDSL-EPR 研究

基本信息

批准号：
7582267
负责人：
PAUL Gillespie FITZGERALD
金额：
$ 29.52万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7582267
关键词：
Accounting Affect Amino Acids Architecture Area Cells Cellular Structures Coiled-Coil Domain Crystallography Cytokeratin Cytoplasm Data Desmin Dialysis procedure Electron Spin Resonance Spectroscopy Event Exhibits Figs - dietary Filament Genes Head Human In Vitro Intermediate Filaments Interruption K-18 conjugate Knowledge Label Left Link Location Maps Membrane Proteins Methods Modeling Monitor Mutation Output Pathologic Pattern Phenotype Physiologic pulse Physiological Point Mutation Positioning Attribute Process Property Proteins Randomized Registries Relative (related person)Reporter Research Design Severities Site Solutions Spin Labels Staging Structure Stuttering Surface Tail Testing Time Translating Urea Vimentin base crosslink dimer disease-causing mutation human disease monomer mutant protein aggregate protein structure research study retinal rods ultra high resolution

项目摘要

Intermediate filaments (IPs) are present in essentially every human cell. However, the inability to achieve crystal structure for intact IF proteins or IFs means that our understanding of IF structure is based in large part on predictions made from primary sequence and from limited cross- linking studies. Thus, most features of commonly presented models of IF structure are experimentally untested, or based on data which is open to alternative interpretation. This places serious limits on our ability to understand normal IF function, and the changes in IF assembly and structure that are caused by the many disease-causing mutations that have been identified in human IF genes. We have demonstrated that site directed spin labeling and electron paramagnetic resonance can provide excellent structural information from intact IFs in physiologic conditions. We propose here to conduct an exhaustive study of the Type III IF protein vimentin, assembling the first comprehensive map of an intact intermediate filament. We will then conduct similar experiments on another Type III IF protein, desmin, and on cytokeratin IFs made from K8 and K18 to determine the degree to which IF assembly and structure are conserved among the three most common forms of intermediate filaments. These studies will map the location and boundaries of alpha-helical, coiled-coil domains, linker regions, the conserved "stutter" found in all IF proteins, the boundaries of the rod domain, the surfaces of apposition between monomers in dimers, and between dinners in intact filaments, the registry and orientation of these dimers, and the sites of IF proteins that are available at the surface of the IF for interactions with other cellular proteins/structures. Sites within the head and tail domains that interact with one another, and with the rod domain will be mapped as well. Finally, we will explore the impact of known disease-causing mutations on IF assembly and structure.

中间丝（IPs）基本上存在于每个人类细胞中。然而,