Mechanism of protein aggregate recognition and disassembly by molecular chaperones

分子伴侣识别和拆卸蛋白质聚集体的机制

基本信息

  • 批准号:
    10246977
  • 负责人:
  • 金额:
    $ 31.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-20 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION: The misfolding and aggregation of essential cellular proteins is a fundamental problem for all living organisms. Aggregation of even non-essential proteins can lead to debilitating diseases like type II diabetes, Alzheimer's, Huntington's and Parkinson's diseases. Importantly, protein folding and aggregation are heavily influenced by the cellular protein quality control machinery, involving networks of molecular chaperones. Precisely how different chaperone systems cooperate to dismantle and reactivate aggregated proteins, and how molecular chaperone action affects disease progression, is not well understood. This proposal will address three fundamental questions that impact this problem: First, what is the most accurate physical description of protein aggregate disassembly by molecular chaperones? Second, in what way do the structural properties of an aggregate nanoparticle impact how an they are taken apart? Third, how does the critical small heat shock (sHsp) class of molecular chaperones enhance protein aggregate disassembly? Addressing these questions in a detailed and quantitative manner is exceedingly difficult using standard approaches, because the complex and heterogeneous nature of protein aggregates can obscure key intermediates and transitions. Single particle analysis, in particular a fluorescence technique known as Burst Analysis Spectroscopy (BAS), is ideally suited to overcome this problem. BAS can quantify complex nanoparticle distributions in free solution, allowing for the detection of dynamically populated intermediates and sub-populations. This project will employ BAS to study the disassembly of protein aggregates by two model disaggregase systems, one from bacteria and one from yeast, at a level of detail unreachable by other approaches. The overall goal is to develop a mechanistic understanding of how different molecular chaperone networks recognize and dismantle protein aggregates that possess distinct physical properties. In service of this goal, this project will extend the capabilities of BAS to incorporate multi-color and Förster resonance energy transfer measurements. This project will also develop a set of new approaches that are complementary to BAS and permit more detailed analysis of the hydrodynamic and structural properties of aggregate nanoparticles by using (1) horizontal light sheet excitation and particle tracking in microfluidic flow and (2) Tip-Enhanced Raman spectroscopy (TERS). It is anticipated that the combination of these techniques will provide uniquely powerful approach to understanding protein disaggregation. Additionally, because the core components of the chaperone networks examined in this work are conserved, it is further expected that the discoveries made in these studies will contribute to a fundamentally better understanding of how molecular chaperones recognize and process protein aggregates in human cells impacted by protein misfolding diseases.
基本细胞蛋白的错误折叠和聚集是所有人的基本问题

项目成果

期刊论文数量(0)
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HAYS S RYE其他文献

HAYS S RYE的其他文献

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{{ truncateString('HAYS S RYE', 18)}}的其他基金

Mechanism of protein aggregate recognition and disassembly by molecular chaperones
分子伴侣识别和拆卸蛋白质聚集体的机制
  • 批准号:
    10020422
  • 财政年份:
    2019
  • 资助金额:
    $ 31.01万
  • 项目类别:
Mechanism of protein aggregate recognition and disassembly by molecular chaperones
分子伴侣识别和拆卸蛋白质聚集体的机制
  • 批准号:
    10581972
  • 财政年份:
    2019
  • 资助金额:
    $ 31.01万
  • 项目类别:
Mechanism of membrane fission at the recycling endosome
回收内体的膜裂变机制
  • 批准号:
    8861439
  • 财政年份:
    2015
  • 资助金额:
    $ 31.01万
  • 项目类别:
Mechanism of membrane fission at the recycling endosome
回收内体的膜裂变机制
  • 批准号:
    9331711
  • 财政年份:
    2015
  • 资助金额:
    $ 31.01万
  • 项目类别:
Mechanism of membrane fission at the recycling endosome
回收内体的膜裂变机制
  • 批准号:
    9275782
  • 财政年份:
    2015
  • 资助金额:
    $ 31.01万
  • 项目类别:
Mechanism of membrane fission at the recycling endosome
回收内体的膜裂变机制
  • 批准号:
    9135458
  • 财政年份:
    2015
  • 资助金额:
    $ 31.01万
  • 项目类别:
GROEL VARIANT: EL43PY
GROEL 变体:EL43PY
  • 批准号:
    8168594
  • 财政年份:
    2010
  • 资助金额:
    $ 31.01万
  • 项目类别:
Mechanism of protein folding intermediate disaggregation by molecular chaperones
分子伴侣蛋白质折叠中间解聚机制
  • 批准号:
    8070448
  • 财政年份:
    2003
  • 资助金额:
    $ 31.01万
  • 项目类别:
Mechanisms of Chaperonin-Mediated Protein Folding
伴侣蛋白介导的蛋白质折叠机制
  • 批准号:
    7228251
  • 财政年份:
    2003
  • 资助金额:
    $ 31.01万
  • 项目类别:
Mechanisms of Chaperonin-Mediated Protein Folding
伴侣蛋白介导的蛋白质折叠机制
  • 批准号:
    6891242
  • 财政年份:
    2003
  • 资助金额:
    $ 31.01万
  • 项目类别:

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