Inositol hexakisphosphate regulation of N-terminal acetyltransfearases

项目摘要 这项相互竞争的更新拨款的首要目标是阐明信号通路和 细胞对环境变化产生选择性反应的机制。细胞内信号传递 途径，如肌醇磷酸(IP)信使，是生物学和IP先天错误的关键调节者 网络会导致疾病。超过80个基因致力于IP的合成和分解 信使。虽然人们对IP新陈代谢了解很多，但关于IP如何代谢的信息却很少 也就是说，什么是受体，IP结合是如何改变它们的 功能呢？我们实验室开发了一种识别IP信号解码器的新方法，并已做出了 关键发现是六磷酸肌醇(IP6)是一种结构上结合的成分和几种 古代N-末端乙酰转移酶家族的成员，称为NAT。这项提案的重点是 为了严格定义IP6和其他代谢物影响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。中概述的工作 这一提议将有助于对细胞如何利用脂质衍生的肌醇信使 增强信号生物学的规范性、特异性和复杂性。

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.