RUI: Mapping lysine deacetylase substrate selectivity

RUI：绘制赖氨酸脱乙酰酶底物选择性

• 批准号: 2309093
• 负责人: Terry Watt
• 金额: $ 68.42万
• 依托单位: Xavier University of Louisiana
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2309093&HistoricalAwards=false
• 关键词: RUI; Mapping; lysine; deacetylase; substrate

The goal of this research project is to understand how a group of enzymes, namely lysine deacetylases, control biological processes in cells. This project will also provide experimental approaches that can be applied to related avenues of research, with subsequent impact on understanding of fundamental biology and medicine. The activities in this project will be performed primarily by undergraduate students and recent graduates from underrepresented groups in scientific fields. Students and recent graduate technicians will gain meaningful research skills and training relevant for progression into graduate programs and the scientific workforce.Lysine deacetylases (KDACs or HDACs) are a family of closely related enzymes that regulate post-translational acetylation of proteins through removal of acetyl groups from lysine residues. The overall goal of this research is to understand how four KDACs regulate cellular activity, by (1) identifying the molecular interactions of KDACs that determine substrate selectivity, and (2) identifying the specific KDAC responsible for deacetylation of particular acetylated lysine residues in non-histone proteins. A combination of in vitro activity assays, molecular dynamics simulations, and a cell-based approach involving genetically encoded but catalytically inactive KDACs will lead to identification of cellular substrates and a detailed understanding of the particular molecular interactions driving activity between a specific KDAC and the acetylated protein. Overall, the project will result in a physical map of the surface of each KDAC that determines selectivity, as well as definitive substrate identification leading to a conceptual map of the cellular processes controlled by the KDACs via their substrates.This project is jointly funded by the Molecular Biophysics cluster in the Division of Molecular and Cellular Biosciences (MCB) and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该研究项目的目标是了解一组酶，即赖氨酸脱乙酰酶，如何控制细胞中的生物过程。 该项目还将提供可应用于相关研究途径的实验方法，并对基础生物学和医学的理解产生后续影响。 该项目的活动将主要由科学领域代表性不足群体的本科生和应届毕业生开展。 赖氨酸脱乙酰基酶（KDAC或HDAC）是一个密切相关的酶家族，通过从赖氨酸残基上去除乙酰基来调节蛋白质的翻译后乙酰化。 本研究的总体目标是了解四种KDAC如何调节细胞活性，通过（1）确定KDAC的分子相互作用决定底物选择性，（2）确定负责非组蛋白中特定乙酰化赖氨酸残基脱乙酰化的特定KDAC。 体外活性测定，分子动力学模拟和基于细胞的方法，涉及遗传编码，但催化失活的KDAC的组合将导致识别细胞底物和详细了解特定的KDAC和乙酰化蛋白质之间的特定分子相互作用驱动活性。 总的来说，该项目将产生一个确定选择性的每个KDAC表面的物理图，该项目由分子和细胞生物科学部（MCB）的分子生物物理学小组和刺激竞争研究的既定计划（EPSCoR）共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。