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Studies on Protein Lipidation

蛋白质脂化研究

基本信息

批准号：
9279154
负责人：
Howard C Hang
金额：
$ 36.27万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9279154
关键词：
Acylation Acyltransferase Address Alkynes Animal Model Antiviral Agents Applications Grants Bacteria Biochemical Bioinformatics Biological Biological Assay Biology Cell Line Cells Cellular biology Chemicals Complex Cysteine Dendritic Cells Detection Eukaryota Fatty Acids Genomics Goals Grant Host Defense Host resistance Human Immunity In Vitro Infection Influenza A virus Integral Membrane Protein Integration Host Factors Interferons Label Laboratories Life Ligation Lipids Mammalian Cell Membrane Metabolic Methods Mus Palmitic Acids Pathway interactions Phenotype Protein Analysis Protein Biochemistry Protein Isoforms Protein S Proteins Proteomics Reagent Reporter Resistance Role Series Signal Pathway Site Virus Diseases Yeasts base biophysical analysis cell type combat esterase fatty acylation influenzavirus microbial mutant novel palmitoylation predictive tools public health relevance reconstitution tool

项目摘要

DESCRIPTION (provided by applicant): Lipid chemical reporters and bioorthogonal ligation methods developed by my laboratory have provided new opportunities to investigate the functions of lipid-modified proteins in biology. Our proteomic analysis of fatty-acylated proteins in dendritic cells using fatty acid chemical reporters and bioorthogonal chemical proteomics has revealed a new role for protein S-fatty-acylation in host defense against viral infections. We discovered that S-fatty-acylation of membrane-proximal cysteines on murine IFITM3 is crucial for its membrane localization and antiviral activity against influenza A virus. The mechanisms that control S-fatty-acylation of human IFITM proteins have not been evaluated and will be addressed in this grant proposal. Aim 1 will evaluate the S-fatty-acylation levels, sites and function of human IFITM isoforms in different cell types/states of activation. Aim 2 describes the characterization of fatty acids covalently attached to human IFITM3 in cells. Aim 3 describes site-specific lipidation and reconstitution of IFITM3 in vitro for detailed biochemical and biophysical studies. Determining the mechanisms that control S-fatty-acylation IFITM3 function is crucial for understanding host immunity and may reveal new strategies for combatting virus infection in humans. The chemical approaches described in this grant should provide new reagents and methods for studying fatty-acylated proteins.

描述（由申请人提供）：我的实验室开发的脂质化学报告基因和生物正交连接方法为研究脂质修饰蛋白在生物学中的功能提供了新的机会。我们使用脂肪酸化学报告基因和生物正交化学蛋白质组学对树突状细胞中的脂肪酰化蛋白进行蛋白质组学分析，揭示了蛋白质 S-脂肪酰化在宿主防御病毒感染中的新作用。我们发现小鼠 IFITM3 上近膜半胱氨酸的 S-脂肪酰化对其膜定位和针对甲型流感病毒的抗病毒活性至关重要。控制人类 IFITM 蛋白 S-脂肪酰化的机制尚未得到评估，将在本拨款提案中得到解决。目标 1 将评估人类 IFITM 同工型在不同细胞类型/激活状态中的 S-脂肪酰化水平、位点和功能。目标 2 描述了细胞中与人 IFITM3 共价连接的脂肪酸的特征。目标 3 描述了 IFITM3 的体外位点特异性脂化和重构，以进行详细的生化和生物物理研究。确定控制 S-脂肪酰化 IFITM3 功能的机制对于了解宿主免疫至关重要，并可能揭示对抗人类病毒感染的新策略。这项资助中描述的化学方法应该为研究脂肪酰化蛋白质提供新的试剂和方法。