The CFTR Interactome

CFTR 相互作用组

基本信息

批准号：
9175991
负责人：
John R Yates III
金额：
$ 48.13万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9175991
关键词：
Address Affect Affinity Affinity Chromatography Alzheimer&apos s Disease Amino Acids Anions Antibodies Binding Cell physiology Chemicals Child Childhood Crystallization Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator DNA Sequence Alteration Defect Development Disease Epithelial Epithelial Cells Epithelium Equilibrium Future Heart Histones Homeostasis Individual Inherited Intestines Investigation Isotopes Label Length Lung Lysine Maps Mass Spectrum Analysis Methodology Methods Modification Molecular Molecular Conformation Molecular Medicine Mutate Mutation Nature Nerve Degeneration Pancreas Parkinson Disease Pathology Patients Pharmacotherapy Phenylalanine Physiological Positioning Attribute Post-Translational Modification Site Post-Translational Protein Processing Property Protein Conformation Proteins Pulmonary Emphysema Regulation Regulator Genes Research Site Sodium Chloride Specificity Structure Surface Temperature Tertiary Protein Structure Therapeutic Intervention Tissues Transmembrane Domain Work base cold temperature crosslink follow-up in vivo insight method development novel novel therapeutics protein crosslink protein function protein misfolding protein protein interaction research study three dimensional structure

项目摘要

Project summary Cystic Fibrosis (CF) is one of the most common inherited childhood diseases, impacting 1:4,000 children born in the US (www.cff.org). One of the major breakthroughs in molecular medicine was the discovery by Francis Collins et al. in 1988, that the cause for CF in over 70% of patients was a single genetic mutation, an in-frame deletion of Phenylalanine 508 in the Cystic Fibrosis transmembrane conductance regulator gene (DeltaF508 CFTR). In contrast to wild type CFTR, the mutated ∆F508 CFTR anion channel becomes misfolded, displays a conformational defect, and has little to no activity. Intense research in recent years indicates that the conformational defect caused by the F508 deletion not only impacts protein function, but to a major extent also protein interactions and post-translational modifications (PTMs), and that changes in the specificity and affinity of these interactions may drive the disease. Therefore, huge efforts are being made to develop new compounds that correct the conformational defect, but they are hampered by the fact that the conformational defect of ∆F508 CFTR has not yet been fully characterized. Through the development of novel methods for in vivo structural characterization of proteins by mass spectrometry, investigation of post- translational modifications of CFTR, which influence protein conformation, and development of methods for identification of conformation-specific interactions, we aim to contribute to a better understanding of the conformational defect in CF and its impact on protein-protein interactions in this disease.

项目概要囊性纤维化（CF）是最常见的遗传性儿童疾病之一，影响 1：4,000名儿童在美国出生（www.cff.org）的重大突破之一。分子医学是弗朗西斯·柯林斯 (Francis Collins) 等人于 1988 年发现的。超过 70% 的 CF 患者是单一基因突变，即框内缺失囊性纤维化跨膜电导调节基因中的苯丙氨酸 508 (DeltaF508 CFTR) 与野生型 CFTR 相比，突变的 ΔF508 CFTR 阴离子。通道错误折叠，显示构象缺陷，并且几乎没有近年来的深入研究表明构象缺陷引起的。 F508 缺失不仅影响蛋白质功能，而且在很大程度上影响蛋白质相互作用和翻译后修饰（PTM），并且改变因此，这些相互作用的特异性和亲和力可能会导致疾病的发生。正在开发纠正构象的新化合物缺陷，但它们受到以下事实的阻碍：ΔF508 CFTR 的构象缺陷尚未通过开发新方法得到充分表征。通过质谱分析蛋白质的体内结构表征，后研究 CFTR 的翻译修饰会影响蛋白质构象，以及开发识别构象特异性相互作用的方法，我们的目标有助于更好地理解 CF 的构象缺陷及其影响关于这种疾病中蛋白质-蛋白质相互作用的研究。