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Structural Characterization of Prion Isoforms in Multiple TSE Diseases

多种 TSE 疾病中朊病毒亚型的结构特征

基本信息

批准号：
8245069
负责人：
Michele Ann McGuirl
金额：
$ 27.55万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8245069
关键词：
Affect Amyloid Proteins Bovine Spongiform Encephalopathy Brain C-terminal Cattle Characteristics Chemicals Creutzfeldt-Jakob Syndrome Detection Deuterium Disease Electron Microscopy Electrons Environment Family Fatal Familial Insomnia Gerstmann-Straussler-Scheinker Disease Glean Goals Health Human Hydrogen Individual Inherited Kuru Label Length Mammals Maps Mass Spectrum Analysis Membrane Membrane Proteins Methods Modeling Molecular Conformation Mutation N-terminal Nature Neurodegenerative Disorders Peptide Fragments PrPSc Proteins Prion Diseases Prions Property Protein Isoforms Protein Subunits Proteins Publishing Recombinants Relative (related person)Reporter Research Resolution Scrapie Series Sheep Site Spectrum Analysis Spin Labels Structure Surveys Techniques Testing Tissues Variant Vertebral column Work X-Ray Crystallography base chronic wasting disease of elk and deer crosslink disease transmission interest mutant prevent protein function protein misfolding research study solute synuclein tau Proteins trend

项目摘要

DESCRIPTION (provided by applicant): The goal of this research is to elucidate the structure of the prion protein in its aggregated isoforms, and to elucidate the relationship between isoform structure and different types of prion diseases. Prion protein is the causative agent of many fatal neurodegenerative diseases of mammals. These diseases are characterized by the conversion of normal, monomeric prion protein (PrPC) to a misfolded conformational state that aggregates and accumulates as fibrillar plaques in the brain. Transmission of the disease can occur when one mammal ingests the infected tissue of another. When exposed to an infectious aggregate, normal PrPC takes on the misfolded conformation and the fibrils are thus propagated. Any treatment of a prion disease must prevent or abrogate misfolding/aggregation while not affecting normal PrP function. Hence, it is important to understand the structural differences between the PrP isofoms. High resolution structures of PrPC from many mammals have been determined by both NMR and X-ray crystallography. In contrast, the insoluble, fibrillar nature of the infectious form has hampered the elucidation of its structural details. However, numerous biophysical and spectroscopic studies suggest that the misfolded form contains a much higher proportion of ¿-sheet than normal PrP, which is mostly a-helical/random coil. This work will elucidate the nature of the PrP subunit interactions in several forms of recombinant PrP by using two biophysical techniques: site directed spin labeling (SDSL) combined with electron paramagnetic spectroscopy (EPR) and site directed crosslinking combined with mass spectrometry (MS). The EPR experiments provide information on protein backbone dynamics, secondary, tertiary, and quaternary structure, distances between labeled residues, and the mobility of the label itself. The crosslinking experiments will confirm the structural information gleaned from EPR. PUBLIC HEALTH RELEVANCE The elucidation of the details of the structure of prion fibrils will be of great value in developing treatments for prion diseases, which are fatal neurodegenerative diseases of mammals. These include Creutzfeldt-Jakob disease (CJD) and variant CJD, Gerstmann- Straussler-Scheinker disease, Fatal Familial Insomnia, and kuru (humans), scrapie (sheep), chronic wasting disease (elk, deer), and mad cow disease (cattle). Treatment of any prion disease must prevent or abrogate fibril formation while not affecting normal prion function; hence, it is important to understand the structural differences among the different prion isofoms.

描述（由申请人提供）：本研究的目的是阐明朊病毒蛋白聚集异构体的结构，阐明异构体结构与不同类型朊病毒疾病的关系。朊蛋白是哺乳动物许多致死性神经退行性疾病的病原体。这些疾病的特征是正常的单体朊蛋白（PrPC）转化为错误折叠的构象状态，在大脑中聚集和积累为纤维斑块。当一种哺乳动物吞食另一种哺乳动物的受感染组织时，就会发生疾病的传播。当暴露于传染性聚集体时，正常的PrPC呈现错误折叠的构象，原纤维因此繁殖。朊病毒疾病的任何治疗必须在不影响正常PrP功能的情况下防止或消除错误折叠/聚集。因此，了解PrP异构体之间的结构差异是很重要的。通过核磁共振和x射线晶体学测定了许多哺乳动物PrPC的高分辨率结构。相反，传染性形式的不溶性、纤原性阻碍了对其结构细节的阐明。然而，大量的生物物理和光谱研究表明，错误折叠形式含有比正常PrP更高比例的¿-sheet，后者主要是a-螺旋/随机线圈。本工作将通过使用两种生物物理技术：位点定向自旋标记（SDSL）结合电子顺磁谱（EPR）和位点定向交联结合质谱（MS）来阐明几种形式重组PrP亚基相互作用的性质。EPR实验提供了蛋白质骨架动力学、二级、三级和四级结构、标记残基之间的距离以及标记本身的迁移性等信息。交联实验将证实从EPR中收集到的结构信息。朊病毒是哺乳动物致命的神经退行性疾病，阐明朊病毒原纤维的结构细节对开发治疗方法具有重要价值。这些疾病包括克雅氏病（CJD）和变异型CJD， Gerstmann- Straussler-Scheinker病，致命性家族性失眠症，库鲁病（人类），痒病（羊），慢性消耗性疾病（麋鹿，鹿）和疯牛病（牛）。任何朊病毒疾病的治疗必须在不影响正常朊病毒功能的情况下防止或消除原纤维的形成；因此，了解不同朊病毒异构体之间的结构差异是很重要的。