Inositol hexakisphosphate regulation of N-terminal acetyltransfearases

N-末端乙酰转移酶的肌醇六磷酸调节

• 批准号: 9927656
• 负责人: John D. York
• 金额: $ 39.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927656
• 关键词: Acetylation; Acetyltransferase; Basic Science; Binding; Biochemical; Biological Process; Biology; Cell Line; Cell physiology; Cells; Cellular biology; Code; Complex; Coupled; Data; Disease; Environment; Enzymatic Biochemistry; Family; Family member; Functional disorder; Genes; Genetic; Goals; Grant; Hereditary Disease; Human; Inositol; Inositol Phosphate Metabolism Pathway; Inositol Phosphates; Kinetics; Laboratories; Link; Lipids; Mediating; Metabolic; Metabolism; Methods; Molecular Chaperones; Molecular Conformation; N-terminal; Phytic Acid; Protein Acetylation; Proteins; Public Health; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Specificity; Structure; Substrate Specificity; System; Work; Yeasts; addiction; base; improved; insight; member; novel; protein folding; receptor; recruit; response; structural biology

Project Summary The overarching goal of this competing renewal grant is the elucidation of signaling pathways and the mechanisms by which cells elicit selective responses to changes in their environment. Intracellular signaling pathways, such as inositol phosphate (IP) messengers, are key regulators of biology and inborn errors in IP networks result in disease. Over eighty genes are dedicated to the synthesis and breakdown of IP messengers. While much is know about IP metabolism, less information is available as to how the ensemble of dozens of IP molecules are decoded: that is, what are the receptors and how does IP binding alter their function? Our laboratory has developed a new method for identifying decoders of IP signals and has made a key discovery that inositol hexakisphosphate (IP6) is a structurally bound component and regulator of several members of the ancient family of N-terminal acetyltransferases, known as NATs. The focus of this proposal is to rigorously define the mechanisms by which IP6 and other metabolites influence NAT structure and function, and ultimately alter protein N-terminal acetylation in normal and disease cellular states. The work outlined in this proposal will contribute fundamental insights into how cells use lipid-derived inositol messengers to enhance regulation, specificity and complexity of signaling biology.

项目摘要 这项竞争更新赠款的总体目标是阐明信号通路和 细胞引起对环境变化的选择性响应的机制。细胞内信号传导 途径，例如磷酸肌醇（IP）信使，是IP中生物学和先天错误的关键调节剂 网络导致疾病。超过80个基因专门用于IP的合成和分解 使者。虽然对IP代谢有很多了解，但有关合奏的信息的信息较少 数十个IP分子被解码：也就是说，受体是什么，IP结合如何改变其 功能？我们的实验室已经开发了一种新方法来识别IP信号的解码器，并制作了 关键发现，肌醇六磷酸（IP6）是几个结构上约束的组件和调节剂 N末端乙酰转移酶的古代家族的成员，称为NAT。该提议的重点是 严格定义IP6和其他代谢产物影响NAT结构和功能的机制， 并最终改变正常和疾病细胞状态下的蛋白质N末端乙酰化。概述的工作 该建议将对细胞如何使用脂质衍生的肌醇使者进行基本见解 提高信号生物学的调节，特异性和复杂性。