RUI: Mapping lysine deacetylase substrate selectivity

这个研究项目的目标是了解一组酶，即赖氨酸脱乙酰酶，是如何控制细胞中的生物过程的。该项目还将提供可应用于相关研究途径的实验方法，并随后对基础生物学和医学的理解产生影响。该项目的活动将主要由科学领域中代表性不足群体的本科生和应届毕业生进行。学生和新近毕业的技术人员将获得与进入研究生课程和科学工作相关的有意义的研究技能和培训。赖氨酸脱乙酰酶(KDAC或HDAC)是一类密切相关的酶，通过从赖氨酸残基中去除乙酰基来调节蛋白质翻译后的乙酰化。本研究的总体目标是通过(1)确定决定底物选择性的KDAC的分子相互作用，以及(2)确定负责非组蛋白蛋白中特定乙酰化赖氨酸残基脱乙酰基的特定KDAC，了解四个KDAC如何调节细胞活性。结合体外活性分析、分子动力学模拟和基于细胞的方法，包括基因编码但催化不活性的KDAC，将导致识别细胞底物和详细了解特定KDAC和乙酰化蛋白质之间驱动活性的特定分子相互作用。总体而言，该项目将产生决定选择性的每个KDAC表面的物理图，以及最终的底物识别，从而产生KDAC通过其底物控制的细胞过程的概念图。该项目由分子和细胞生物科学部(MCB)的分子生物物理学集群和既定的刺激竞争研究计划(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智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.