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.

项目摘要囊性纤维化（CF）是最常见的儿童疾病之一，影响 1：4,000名在美国出生的孩子（www.cff.org）。主要突破之一分子医学是弗朗西斯·柯林斯（Francis Collins）等人的发现。 1988年，这是原因对于超过70％的患者，CF是单个遗传突变，框内缺失的囊性纤维化跨膜电导基因的苯丙氨酸508 （Deltaf508 CFTR）。与野生型CFTR相反，突变的∆F508 CFTR阴离子渠道被错误折叠，显示构象缺陷，几乎没有活动。近年来的激烈研究表明，构象缺陷引起通过F508缺失，不仅会影响蛋白质功能，而且在很大程度上还会影响蛋白质相互作用和翻译后修改（PTMS），并改变这些相互作用的特异性和亲和力可能会推动疾病。因此，巨大正在努力开发纠正构象的新化合物缺陷，但由于ΔF508CFTR的构象缺陷而受到阻碍尚未完全表征。通过开发新的方法通过质谱法对蛋白质的体内结构表征，研究后的研究 CFTR的翻译修饰，会影响蛋白质构象，并开发用于识别特定构象相互作用的方法，我们的目标有助于更好地理解CF及其影响的构象缺陷关于该疾病中蛋白质 - 蛋白质相互作用。