CFTR 相互作用组-猫眼课题宝

CFTR 相互作用组

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

项目状态：

已结题

起止时间：

2016-06-01 至 2020-04-30

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

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中文摘要

翻译

项目摘要囊性纤维化（CF）是最常见的遗传性儿童疾病之一， 1：4,000在美国出生的孩子（www.cff.org）。其中一个重大突破，分子医学是弗朗西斯柯林斯等人在1988年发现的，超过70%的患者的CF是一个单一的基因突变，一个框内缺失，囊性纤维化跨膜传导调节因子基因中的苯丙氨酸508 （DeltaF508 CFTR）。与野生型CFTR相反，突变的CFNF 508 CFTR阴离子通道变得错误折叠，显示构象缺陷，并且几乎没有活动近年来的大量研究表明， F508缺失不仅影响蛋白质功能，而且在很大程度上也影响蛋白质功能。相互作用和翻译后修饰（PTM），以及这些相互作用的特异性和亲和性可能驱动疾病。因此，巨大人们正在努力开发新的化合物，缺陷，但它们受到以下事实的阻碍：还没有被完全定性。通过开发新的方法，用质谱法对蛋白质进行体内结构表征， CFTR的翻译修饰，其影响蛋白质构象，以及开发用于鉴定构象特异性相互作用的方法，我们的目标是有助于更好地了解CF中的构象缺陷及其影响蛋白质间相互作用的研究

英文摘要

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.

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