DEVELOPMENT OF MEMBRANE GLYCOPROTEIN STRUCTURE

膜糖蛋白结构的发育

基本信息

  • 批准号:
    6041263
  • 负责人:
  • 金额:
    $ 24.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1996
  • 资助国家:
    美国
  • 起止时间:
    1996-02-10 至 2005-01-31
  • 项目状态:
    已结题

项目摘要

The long-range objectives of this study are to understand the manner in which folding information is encoded in the primary sequence of membrane proteins and the means by which the cell recognizes when this process of information transfer has failed. The studies of the cystic fibrosis transmembrane conductance regulator (CFTR) supported by this grant entering its fourth year, have provided fundamental information relevant to understanding the nature of the AF508 folding mutant responsible for most cases of cystic fibrosis and the proteins which transiently interact with CFTR to assist efficient folding. Future studies will focus on elucidation of the conformation of critical folding intermediates, the machinery that recognizes these intermediates, and the later steps in folding, namely the association of CFTR with other proteins to form macromolecular complexes at the membrane. To this end the five specific aims are to: 1. Characterize the structure of the CFTR foldina intermediate altered bv the AF508 mutation. Established biophysical methods will be employed to characterize the structural features of the critical folding intermediate. 2. Identify the protein machinery required for recognition of the folding intermediate and characterize their mechanism of action. The proteins required for recognition of the critical folding intermediate in vivo will be isolated using our recently developed in vitro proteolysis assay which distinguishes mutant from wild type protein during folding. 3. Determine the folding pathway of the first transmembrane domain of CFTR and the effect of disease-causing mutations. Peptide models of the transmembrane spans of CFTR and an in vitro translation system will be utilized to study the membrane-integration and helical-association steps of the wild type and mutant transmembrane domains. 4. Identity the proteins that recognize misfolded transmembrane domains and determine their mechanism of action. Site specific-crosslinking and high stringency immunoprecipitations will be used to identify proteins that interact with misfolded mutant transmembrane domains of CFTR. 5. Characterize the interaction of CFTR with other proteins during maturation to form a supramolecular complex. Based on our recent finding that CFTR activates the anion exhanger in CFTR expressing cells and tissues, we will test the hypothesis that these proteins associate to form a large quartemary structure during the last steps of folding. To accomplish these goals, a combination of biochemical, biophysical, immunochemical, molecular and cell biological approaches, all established in this laboratory, will be employed. These studies are necessary for and fundamental to a detailed understanding of the mechanisms by which membrane proteins fold.
这项研究的长期目标是了解折叠信息在膜蛋白一级序列中编码的方式,以及当信息传递过程失败时细胞识别的方式。该基金支持的囊性纤维化跨膜传导调节因子(CFTR)的研究已进入第四个年头,提供了与理解AF508折叠突变体的性质相关的基本信息,该突变体负责大多数囊性纤维化病例,以及与CFTR短暂相互作用以帮助有效折叠的蛋白质。未来的研究将集中在阐明关键折叠中间体的构象,识别这些中间体的机制,以及折叠的后期步骤,即CFTR与其他蛋白质在膜上形成大分子复合物的结合。为此,五个具体目标是:1。表征由AF 508突变改变的CFTR折叠蛋白中间体的结构。将采用已建立的生物物理方法来表征关键折叠中间体的结构特征。2.识别折叠中间体所需的蛋白质机制,并表征其作用机制。将使用我们最近开发的体外蛋白质水解测定法分离用于识别体内关键折叠中间体所需的蛋白质,该测定法在折叠期间区分突变体和野生型蛋白质。3.确定CFTR第一个跨膜结构域的折叠途径和致病突变的影响。将利用CFTR跨膜跨度的肽模型和体外翻译系统来研究野生型和突变跨膜结构域的膜整合和螺旋缔合步骤。4.识别识别错误折叠的跨膜结构域的蛋白质并确定其作用机制。位点特异性交联和高严格性免疫沉淀将用于鉴定与CFTR的错误折叠突变跨膜结构域相互作用的蛋白质。5.表征CFTR在成熟过程中与其他蛋白质的相互作用,以形成超分子复合物。基于我们最近发现CFTR激活CFTR表达细胞和组织中的阴离子交换剂,我们将测试这些蛋白质在折叠的最后步骤中缔合形成大的四元结构的假设。为了实现这些目标,将采用生物化学,生物物理,免疫化学,分子和细胞生物学方法的组合,所有这些方法都在本实验室建立。这些研究对于详细了解膜蛋白折叠的机制是必要的和基本的。

项目成果

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PHILIP J THOMAS其他文献

PHILIP J THOMAS的其他文献

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{{ truncateString('PHILIP J THOMAS', 18)}}的其他基金

DEVELOPMENT OF MEMBRANE PROTEIN STRUCTURE
膜蛋白结构的发育
  • 批准号:
    7992507
  • 财政年份:
    2010
  • 资助金额:
    $ 24.19万
  • 项目类别:
Molecular Mechanisms of Ion Transport by the SMG
SMG 离子传输的分子机制
  • 批准号:
    8064727
  • 财政年份:
    1997
  • 资助金额:
    $ 24.19万
  • 项目类别:
Molecular Mechanisms of Ion Transport by the SMG
SMG 离子传输的分子机制
  • 批准号:
    7826631
  • 财政年份:
    1997
  • 资助金额:
    $ 24.19万
  • 项目类别:
DEVELOPMENT OF MEMBRANE PROTEIN STRUCTURE
膜蛋白结构的发育
  • 批准号:
    8628109
  • 财政年份:
    1996
  • 资助金额:
    $ 24.19万
  • 项目类别:
DEVELOPMENT OF MEMBRANE GLYCOPROTEIN STRUCTURE
膜糖蛋白结构的发育
  • 批准号:
    2150766
  • 财政年份:
    1996
  • 资助金额:
    $ 24.19万
  • 项目类别:
DEVELOPMENT OF MEMBRANE GLYCOPROTEIN STRUCTURE
膜糖蛋白结构的发育
  • 批准号:
    6498102
  • 财政年份:
    1996
  • 资助金额:
    $ 24.19万
  • 项目类别:
Development of Membrane Protein Structure
膜蛋白结构的发展
  • 批准号:
    7179344
  • 财政年份:
    1996
  • 资助金额:
    $ 24.19万
  • 项目类别:
DEVELOPMENT OF MEMBRANE PROTEIN STRUCTURE
膜蛋白结构的发育
  • 批准号:
    8576145
  • 财政年份:
    1996
  • 资助金额:
    $ 24.19万
  • 项目类别:
DEVELOPMENT OF MEMBRANE PROTEIN STRUCTURE
膜蛋白结构的发育
  • 批准号:
    9267978
  • 财政年份:
    1996
  • 资助金额:
    $ 24.19万
  • 项目类别:
DEVELOPMENT OF MEMBRANE GLYCOPROTEIN STRUCTURE
膜糖蛋白结构的发育
  • 批准号:
    6628533
  • 财政年份:
    1996
  • 资助金额:
    $ 24.19万
  • 项目类别:

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