Functions of Tocopherol Transfer Protein

生育酚转移蛋白的功能

基本信息

批准号：
7388147
负责人：
DANNY MANOR
金额：
$ 24.51万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-15 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7388147
关键词：
Address Affinity Amino Acids Antioxidants Binding Binding Proteins Biochemical Biochemistry Biological Biological Assay Biological Process Cell model Cells Characteristics Cultured Cells Cytosol Defect Environment Enzymes Event Exhibits Fatty acid glycerol esters Genes Health Hepatic Hepatocyte Human In Vitro Investigation Lead Ligand Binding Ligands Localized Location Mediating Mediator of activation protein Membrane Metabolic Metabolism Molecular Mutation Numbers Optics Organic Chemistry Pathology Pattern Physiological Population Property Protein Biochemistry Proteins Role Signal Transduction Site Site-Directed Mutagenesis Structure Structure-Activity Relationship Synthesis Chemistry Time Tocopherols Transmembrane Transport Vitamin E Vitamin E Deficiency Vitamins Water analytical method aqueous base design hepatoma cell improved in vivo insight intracellular protein transport mutant novel protein localization location research study stable isotope thymidine 5&apos -triphosphate transcription factor

Address Affinity Amino Acids Antioxidants Binding Binding Proteins Biochemical Biochemistry Biological Biological Assay Biological Process Cell model Cells Characteristics Cultured Cells Cytosol Defect Environment Enzymes Event Exhibits Fatty acid glycerol esters Genes Health Hepatic Hepatocyte Human In Vitro Investigation Lead Ligand Binding Ligands Localized Location Mediating Mediator of activation protein Membrane Metabolic Metabolism Molecular Mutation Numbers Optics Organic Chemistry Pathology Pattern Physiological Population Property Protein Biochemistry Proteins Role Signal Transduction Site Site-Directed Mutagenesis Structure Structure-Activity Relationship Synthesis Chemistry Time Tocopherols Transmembrane Transport Vitamin E Vitamin E Deficiency Vitamins Water analytical method aqueous base design hepatoma cell improved in vivo insight intracellular protein transport mutant novel protein localization location research study stable isotope thymidine 5&apos -triphosphate transcription factor

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项目摘要

DESCRIPTION (provided by applicant): Vitamin E (tocopherol) is the major fat-soluble antioxidant in humans. However, surprisingly little is known about the fate of this molecule once it enters target cells, or about the molecular events by which its storage, metabolism, and biological functions are regulated. As tocopherols are poorly soluble in water, it is believed that specific binding proteins are critical mediators of vitamin E function by virtue of their ability to solubilize and transport their ligand in the aqueous environment of the cell. Here, we propose to study the tocopherol transfer protein (aTTP) in order to gain insights into its biological role(s) and, in turn, into the mode of action of vitamin E. We will use our combined expertise in synthetic chemistry, stable-isotope analysis, protein biochemistry, and intra-cellular signaling to elucidate the functions of aTTP in mediating the biological activities of vitamin E. Specifically, we propose to address three specific aims: 1)- to characterize the structure/function relationship in aTTP in vitro. Using novel optical activity assays and site-directed mutagenesis, we will obtain molecular- level understanding of ligand binding and transfer activities of aTTP, and of the naturally occurring mutations in this protein. 2)- To characterize the structure/function relationship in aTTP in vivo. We will examine the effects of naturally occurring mutations in aTTP on tocopherol secretion from cultured hepatocytes. 3)- To identify proteins that interact with aTTP in a tocopherol dependent manner, and to determine the sub-cellular localization of the protein. Studies proposed in this application will provide critical information that is likely to improve our understanding of vitamin E function as a mediator of human health.

描述（由申请人提供）：维生素E（生育酚）是人类的主要脂溶性抗氧化剂。然而，一旦该分子进入靶细胞，或者对其储存，代谢和生物学功能的分子事件，该分子进入靶细胞后的命运知之甚少。由于生育酚在水中易于溶解，因此人们认为特定的结合蛋白是维生素E功能的关键介体，因为它们能够在细胞的水性环境中溶解并运输其配体的能力。 Here, we propose to study the tocopherol transfer protein (aTTP) in order to gain insights into its biological role(s) and, in turn, into the mode of action of vitamin E. We will use our combined expertise in synthetic chemistry, stable-isotope analysis, protein biochemistry, and intra-cellular signaling to elucidate the functions of aTTP in mediating the biological activities of vitamin E. Specifically, we propose要解决三个特定的目的：1） - 表征体外ATTP中的结构/功能关系。使用新型的光学活性测定和定点诱变，我们将获得对ATTP的配体结合和转移活性的分子水平理解，以及该蛋白质中天然发生的突变。 2） - 表征体内ATTP中的结构/功能关系。我们将研究ATTP中自然发生的突变对培养的肝细胞的生育酚分泌的影响。 3） - 鉴定以依赖性的方式鉴定与ATTP相互作用的蛋白质，并确定蛋白质的亚细胞定位。在本应用程序中提出的研究将提供关键信息，这些信息可能会提高我们对维生素E作为人类健康的介体的理解。