Structural Changes and the Function of Ras Oncogenes

Ras 癌基因的结构变化和功能

基本信息

批准号：
7779508
负责人：
Robert J Deschenes
金额：
$ 20.98万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-08-01 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7779508
关键词：
Address Area Binding Biological Assay C-terminal Catalysis Chimeric Proteins Cloning Complementarity Determining Regions Complex Diagnosis Digestion Enzymes Family Funding GTP-Binding Proteins Goals Health Homologous Gene Human In Vitro Incidence Investments Ligands Link Lipids Malignant Neoplasms Maps Mass Spectrum Analysis Measurement Membrane Membrane Proteins Methods Methylation Modification Molecular Molecular Target Mutagenesis Mutate Mutation Orphan Palmitates Palmitoyl Coenzyme A Peptides Phosphorylation Phosphorylation Site Play Positioning Attribute Post-Translational Protein Processing Prevention Property Protein Family Proteins Radiolabeled Reaction Recycling Regulation Role Series Signal Transduction Signal Transduction Pathway Site Site-Directed Mutagenesis Specificity Structure Substrate Specificity Techniques Testing Time Vesicle Work Yeasts Zinc anticancer research base falls farnesylation human disease in vivo inhibitor/antagonist member mutant palmitoylation prenylation protein farnesyltransferase radiotracer ras Oncogene ras Proteins receptor research study trafficking

项目摘要

Ras proteins are evolutionarily conserved, membrane-associated, small GTP binding proteins involved in signal transduction pathways. Given the high incidence of Ras mutations in human cancers, considerable effort has gone into studying the function of Ras proteins and ways to inhibit Ras activity. One particularly promising approach has been to target the enzymes required for the posttranslational addtion of farnesyl and palmitoyl lipids. Farnesylation and the farnesyl transferase (FT) enzymes have been extensively studied, but much less is known about the palmitoylation of Ras or other palmitoylated proteins. The covalent attachment of palmitate to eukaryotic proteins was first described over 30 years ago and since that time the list of acylated proteins has grown. The types of proteins that undergo palmitoylation are quite diverse and include intrinsic and peripherally associated membrane proteins. Palmitoylation is important in receptor trafficking and recycling, protein association with lipid microdomains, vesicle fusion, and signal transduction. While the identification of palmitoylated proteins has proceeded rapidly, understanding of the molecular mechanisms that underlie modification with palmitate has advanced more slowly. The reversibility of palmitoylation raises the possibility that it is a regulatory modification much like protein phosphorylation. During the last funding period, we identified the Ras palmitoyltransferase (PAT). The discovery of the Ras PAT filled a long-standing gap in the field of protein palmitoylation. The current proposal is divided into five specific aims that address basic properties of Ras PAT enzymes including membrane topology, the role of zinc in structure and catalysis, subunit interactions, substrate specificity, and regulation by phosphorylation. This study will provide essential new information about a class of lipid modification enzymes with potential impact to human health. The goals of this study fall within the general area of "Molecular Targets of Prevention, Diagnosis, and Treatment", one of the five priority areas identified in the 2005 National Investment in Cancer Research (NCI).

RAS蛋白在进化上是保守的，与膜相关的小GTP结合蛋白信号转导途径。鉴于人类癌症中RAS突变的发病率很高研究了RAS蛋白的功能以及抑制RAS活性的方法。特别是有前途的方法是针对法尼基和法尼后翻译后所需的酶棕榈酰脂质。 Farnesylation和Farnesyl转移酶（FT）酶已经进行了广泛的研究，但是关于RAS或其他棕榈酰化蛋白的棕榈酰化知之甚少。共价棕榈酸酯与真核蛋白的附着首次描述了30年前，从那时起酰化蛋白的清单已生长。经历棕榈酰化的蛋白质类型非常多样化，包括固有和周围相关的膜蛋白。棕榈酰化在受体中很重要运输和回收利用，蛋白质与脂质微区，囊泡融合和信号转导的关联。虽然棕榈酰化蛋白的鉴定已迅速进行，但对分子的了解棕榈酸酯修饰的基础的机制进展得更慢。可逆性棕榈酰化增加了它是一种像蛋白质磷酸化一样的调节性修饰的可能性。在最后一个资金期间，我们确定了RAS Palmitoyltransferase（PAT）。发现拉斯帕特（Pat）填补了蛋白质棕榈酰化领域的长期差距。当前的提议分为五个针对RAS PAT酶的基本特性的具体目的，包括膜拓扑，结构和催化，亚基相互作用，底物特异性以及通过磷酸化调节的锌。这项研究将提供有关具有潜力的脂质修饰酶的基本新信息对人类健康的影响。这项研究的目标属于“分子靶标的一般区域预防，诊断和治疗”是2005年国家确定的五个优先领域之一投资癌症研究（NCI）。