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Studies on Protein Lipidation

蛋白质脂化研究

基本信息

批准号：
9707092
负责人：
Howard C Hang
金额：
$ 7.87万
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/9707092
关键词：
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 reconstitution tool

项目摘要

PROJECT SUMMARY 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.

项目总结我实验室开发的脂类化学报告和生物正交连接方法提供了新的研究脂质修饰蛋白质在生物学中的功能的机会。我们对脂肪的蛋白质组学分析- 用脂肪酸化学报告和生物正交化学蛋白质组学研究树突状细胞中的酰化蛋白揭示了蛋白质S在宿主防御病毒感染中的新作用-脂肪酰化。我们发现膜-近端半胱氨酸的S-脂肪酰化对小鼠IFITM3膜的影响甲型流感病毒的定位和抗病毒活性。S-脂肪酰化的调控机制人类IFITM蛋白还没有被评估，将在这项赠款提案中讨论。目标1将评价不同细胞类型/状态下人IFITM异构体的S-脂肪酰化水平、位点和功能激活。目的2描述细胞内与人IFITM3共价结合的脂肪酸的特性。目的3描述IFITM3在体外的位点特异性脂化和重组，以进行详细的生化和生物物理学研究。确定控制S-脂肪酰化IFITM3功能的机制对于了解宿主免疫，并可能揭示抗击人类病毒感染的新策略。这个这项资助中描述的化学方法应该为研究脂肪的化学方法提供新的试剂和方法。酰化蛋白质。