BIOPHYSICAL PROPERTIES OF PRION PROTEIN OLIGOMERS

朊病毒蛋白低聚物的生物物理特性

基本信息

  • 批准号:
    7277489
  • 负责人:
  • 金额:
    $ 35.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-06-01 至 2012-05-31
  • 项目状态:
    已结题

项目摘要

The long-term goal of this component of the Program Project is to elucidate the molecular basis of the pathogenic process in transmissible spongiform encephalopathies (TSEs), a group of fatal neurodegenerative diseases that afflict humans and animals. The protein-only model postulates that the infectious pathogen responsible for these diseases is a misfolded form of the prion protein, PrPSc, which self-propagates by binding to normal prion protein and catalyzing its conversion to the pathogenic form. TSE diseases have emerged as a major public health issue following recent epidemics of bovine spongiform encephalopathy (BSE) and indications that BSE might have crossed the species barrier to cause variant Creutzfeldt-Jakobdisease in humans. The main focus of this project is on understanding structural properties of various abnormally folded forms of the recombinaht prion protein. The first specific aim is to determine the structure of amyloid fibrils formed by the recombinant prion protein in vitro at a resolution close to amino acid residue. This will be accomplished using a number of newly emerged biophysical techniques that provide site- specific information about local protein mobility and accessibility and measurements of intermolecular and intramolecular distances between specific sites within the prion protein amyloid. Another specific aim is to expand and optimize the recently developed technique of protein misfolding by cyclic amplification (PMCA) to accomplish efficient brain PrP^-templated conversion of bacterially-expressed recombinant prion protein to proteinase K-resistantform, and assess the infectivity of this product in experimental animals. Finally, building on the experience gained in structural studies with spontaneously formed prion protein amyloid (Specific Aim 1), we will determine structural organization of the recombinant PrP oligomers generated in brain PrPSc- templated PMCA reaction. Our hypothesis is that the basic folding motif of PrPSc is similar to that of PrP amyloid fibrils, though some differences which may account for especially high resistance of brain PrPSc to proteolytic digestion are expected.
该计划项目的这一组成部分的长期目标是阐明 传染性海绵状脑病(TSE)是一组致命的 折磨人类和动物的神经退行性疾病。纯蛋白质模型假设 导致这些疾病的传染性病原体是朊病毒蛋白质的错误折叠形式, PrPSc通过与正常朊病毒蛋白结合并催化其转化为 致病形式。TSE疾病已成为一个主要的公共卫生问题, 牛海绵状脑病(BSE)的流行和BSE可能具有的迹象 跨越了物种屏障,导致了人类的变异型克雅氏病。主要的重点 这个项目的目的是了解各种异常折叠形式的结构特性, 重组朊病毒蛋白。第一个具体目标是确定淀粉样纤维的结构 由重组朊病毒蛋白在体外以接近氨基酸残基的分辨率形成。这将 使用一些新出现的生物物理技术,提供网站- 关于局部蛋白质流动性和可及性的具体信息以及 朊病毒蛋白淀粉样蛋白内特定位点之间的分子间和分子内距离。 另一个具体目标是扩展和优化最近开发的蛋白质技术, 通过循环扩增(PMCA)错误折叠,以实现有效的脑PrP^-模板转化 细菌表达的重组朊病毒蛋白转化为蛋白酶K抗性形式,并评估 本品在实验动物中的感染性。最后,根据2004年取得的经验, 结构研究与自发形成的朊病毒蛋白淀粉样蛋白(具体目标1),我们将 确定脑PrPSc中产生的重组PrP寡聚体的结构组织- 模板化PMCA反应。我们的假设是PrPSc的基本折叠基序与 PrP淀粉样纤维,虽然一些差异可能解释了特别高的耐药性, 脑PrPSc蛋白水解消化。

项目成果

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WITOLD K SUREWICZ其他文献

WITOLD K SUREWICZ的其他文献

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{{ truncateString('WITOLD K SUREWICZ', 18)}}的其他基金

Structural diversity of cervid prions and phenotypic variation of chronic wasting disease
鹿朊病毒的结构多样性和慢性消耗性疾病的表型变异
  • 批准号:
    10657957
  • 财政年份:
    2023
  • 资助金额:
    $ 35.78万
  • 项目类别:
Replication mechanism of human prions
人类朊病毒的复制机制
  • 批准号:
    10330439
  • 财政年份:
    2018
  • 资助金额:
    $ 35.78万
  • 项目类别:
Mechanisms of Transmissibility in Prion Diseases
朊病毒疾病的传播机制
  • 批准号:
    8739928
  • 财政年份:
    2014
  • 资助金额:
    $ 35.78万
  • 项目类别:
Mechanisms of Transmissibility in Prion Diseases
朊病毒疾病的传播机制
  • 批准号:
    9122308
  • 财政年份:
    2014
  • 资助金额:
    $ 35.78万
  • 项目类别:
Mechanisms of Transmissibility in Prion Diseases
朊病毒疾病的传播机制
  • 批准号:
    8930045
  • 财政年份:
    2014
  • 资助金额:
    $ 35.78万
  • 项目类别:
Mechanisms of Transmissibility in Prion Diseases
朊病毒疾病的传播机制
  • 批准号:
    9333168
  • 财政年份:
    2014
  • 资助金额:
    $ 35.78万
  • 项目类别:
Replication mechanism of human prions
人类朊病毒的复制机制
  • 批准号:
    8312479
  • 财政年份:
    2011
  • 资助金额:
    $ 35.78万
  • 项目类别:
Replication mechanism of human prions
人类朊病毒的复制机制
  • 批准号:
    8080743
  • 财政年份:
    2011
  • 资助金额:
    $ 35.78万
  • 项目类别:
Replication mechanism of human prions
人类朊病毒的复制机制
  • 批准号:
    8692032
  • 财政年份:
    2011
  • 资助金额:
    $ 35.78万
  • 项目类别:
Replication mechanism of human prions
人类朊病毒的复制机制
  • 批准号:
    8512826
  • 财政年份:
    2011
  • 资助金额:
    $ 35.78万
  • 项目类别:

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