Role of Proteolysis in Regulating CaaX Protein Function

蛋白水解在调节 CaaX 蛋白功能中的作用

• 批准号: 9352356
• 负责人: Walter K Schmidt
• 金额: $ 28.88万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352356
• 关键词: Affect; Behavior; Biochemical; Biological; Biology; Biophysics; Cell physiology; Cells; Cellular Metabolic Process; Coupled; Coupling; Disease; Drug Design; Drug Targeting; Environment; Enzymes; Event; Family; Gatekeeping; Goals; Guanosine Triphosphate Phosphohydrolases; Investigation; Lead; Lipids; Membrane; Modification; Molecular; Molecular Chaperones; Normal Cell; Oligopeptides; Outcome; Pathway interactions; Peptide Hydrolases; Pheromone; Physiological; Post-Translational Protein Processing; Process; Production; Property; Protein Isoprenylation; Proteins; Proteolysis; Proteolytic Processing; Quality Control; Regulation; Reporter; Research; Research Project Grants; Resistance; Role; Route; Shunt Device; Signaling Protein; Specificity; Structure; Testing; Time; Ursidae Family; Yeasts; a-mating factor; biophysical properties; improved; isoprenylation; novel; prelamin A; prenylation; prevent; protein function; response; shunt pathway; synthetic peptide

PROJECT SUMMARY The goal of this study is to investigate how the properties of proteins are impacted by post-translational modifications (PTMs) associated with protein prenylation, specifically the proteolytic and carboxylmethylation events that typically follow isoprenylation. Most studies to date have investigated this issue using a select few reporters, including the Ras GTPases and the yeast a-factor mating pheromone. Our studies are bringing a new understanding to this issue by promoting a general view that the PTMs occurring to prenylated proteins are not necessarily coupled and are key regulators of protein function and localization. We have proposed two aims. One will investigate the coupling of PTMs using a set of prenylated protein reporters outside those previously studied. Our studies will challenge the conventional paradigm for how prenylated proteins are modified, which in turn will provide guidance to strategies aimed at interfering with protein prenylation and related downstream events as disease therapies. The second aim will investigate the target specificities of the Rce1p and Ste24p proteases that act on prenylated proteins. Our studies will demonstrate that these proteases have very distinct enzymatic profiles, which will provide additional guidance on the specific targeting of these enzymes in disease therapies. We bring to bear on our investigations an exceptionally strong set of preliminary findings, the complementary expertise of several research groups, and a comprehensive molecular toolbox for the study of prenylated proteins and the proteases involved.

项目概要 本研究的目的是研究翻译后如何影响蛋白质的特性 与蛋白质异戊二烯化相关的修饰（PTM），特别是蛋白水解和羧甲基化 通常发生在异戊二烯化之后的事件。迄今为止，大多数研究都使用一些精选的数据来调查这个问题 记者，包括 Ras GTP 酶和酵母 a 因子交配信息素。我们的研究正在带来 通过推广这样一种普遍观点，即异戊二烯化蛋白发生的 PTM，对这个问题有了新的认识 不一定是耦合的，并且是蛋白质功能和定位的关键调节因子。我们提出了两个 目标。人们将使用一组除这些外的异戊二烯化蛋白质报告基因来研究 PTM 的偶联。 以前研究过。我们的研究将挑战异戊二烯化蛋白质的传统范式 修改，这反过来将为旨在干扰蛋白质异戊烯化和 相关的下游事件作为疾病治疗。第二个目标将调查目标的特殊性 作用于异戊二烯化蛋白质的 Rce1p 和 Ste24p 蛋白酶。我们的研究将证明这些 蛋白酶具有非常独特的酶谱，这将为特定靶向提供额外的指导 这些酶在疾病治疗中的作用。我们在调查中采用了一套非常有力的证据 初步研究结果、多个研究小组的互补专业知识以及全面的分子 用于研究异戊二烯化蛋白质和相关蛋白酶的工具箱。