Detection of folding defects in mutant CFTR by ERQC

通过 ERQC 检测突变体 CFTR 的折叠缺陷

• 批准号: 7925382
• 负责人: DOUGLAS M CYR
• 金额: $ 18.67万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925382
• 关键词: Binding; Binding Sites; Cell membrane; Cell surface; Cessation of life; Chemicals; Chronic; Complex; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Cytosol; Data; Defect; Degradation Pathway; Detection; Doctor of Philosophy; Endoplasmic Reticulum; Environment; Failure; Gland; Hydration status; Infection; Knowledge; Lung; Lung diseases; Mediating; Membrane; Membrane Proteins; Modeling; Molecular Chaperones; Monitor; Mutation; Pathway interactions; Play; Proteins; Quality Control; Research Personnel; Roentgen Rays; Role; Signal Transduction; Solvents; Staging; Structure; Surface; System; Testing; Transmembrane Domain; Triage; Ubiquitin; Ubiquitination; multicatalytic endopeptidase complex; mutant; novel; premature; prevent; programs; protein folding; therapeutic development; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Cystic Fibrosis is a fatal lung disease caused by misfolding and premature proteasomal degradation of the mutant Cl- channel CFTRAF508. CFTRAF508 is synthesized in the endoplasmic reticulum (ER), but its folding arrests at an unknown intermediate step and it is selected for degradation prior to passage to the plasma membrane (PM). Loss of CFTR function leads to defects in the hydration of mucosal layers that line glands and airways and chronic infections that death occurs due to lung failure. Hope for the treatment of CF comes from observations that folding defects in CFTRAF508 are rescued by compounds that either alter the cellular folding environment. This competitive renewal application for 2RO1 GM56981 seeks to aid in the development of therapeutics to treat Cystic Fibrosis by elucidating defective steps in the CFTRAF508 folding pathway and identifying ER quality control (ERQC) factors that select CFTRAF508 for degradation. The three major objectives of the proposal are as follows 1. We seek to define the mechanism by which mutations in CFTR cause it to misfold and be degraded the ubiquitin proteasome system. 2. CFTR is a polytopic protein that exposes surfaces in the ER lumen, ER membrane, and cytosol. 'Thus, we will identify the components of the ERQC machinery that sense the folded state of different sub-domains in CFTR. Then, we will determine how the action of the ER localized and cytosolic QC factors is coordinated. 3. We propose to apply the knowledge obtained in our basic studies to develop approaches to block the selection of CFTRAF508 for premature degradation and promote its proper folding. Overall, our studies will provide basic information on protein QC that will aid in the development of therapeutics to treat CF.

描述（由申请人提供）： 囊性纤维化是一种致命的肺疾病，是由于突变cl-通道CFTRAF508的错误折叠和过早蛋白酶体降解引起的。 CFTRAF508是在内质网（ER）中合成的，但是其折叠式停滞在未知的中间步骤中，并在通过到质膜（PM）之前选择降解。 CFTR功能的丧失会导致粘膜层的水合缺陷，这些粘膜层线腺和气道和气道以及由于肺部衰竭而导致死亡的慢性感染。 CF治疗的希望来自观察到CFTRAF508中的折叠缺陷是通过改变细胞折叠环境的化合物来挽救的。这项对2RO1 GM56981的竞争性更新应用旨在帮助开发治疗疗法，通过阐明CFTRAF508折叠途径中的有缺陷步骤来治疗囊性纤维化，并识别ER质量控制（ERQC）因素，以选择CFTRAF508用于脱落。该提案的三个主要目标如下1。我们试图定义CFTR突变导致其错误折叠并降解泛素蛋白酶体系统的机制。 2。CFTR是一种多重蛋白，可暴露在ER腔，ER膜和细胞质中的表面。 ``因此，我们将确定ERQC机械的组件，使CFTR中不同子域的折叠状态。然后，我们将确定如何协调ER局部和胞质QC因子的作用。 3。我们建议应用基础研究中获得的知识来开发方法，以阻止CFTRAF508的选择以进行早产并促进其适当的折叠。总体而言，我们的研究将提供有关蛋白质QC的基本信息，这些信息将有助于开发治疗CF的治疗剂。