EAPSI: Determining the Atomic Structure of Proteins that Form Brain Connections

EAPSI：确定形成大脑连接的蛋白质的原子结构

• 批准号: 1414439
• 负责人: Kevin Gray
• 金额: $ 0.51万
• 依托单位: Gray Kevin T
• 依托单位国家: 美国
• 项目类别: Fellowship Award
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1414439&HistoricalAwards=false
• 关键词: EAPSI; Determining; Atomic; Structure; Proteins

The brain communicates and forms memories through a specialized group of cells called neurons. These cells form connections through extensions called neurites. Neurites are formed when neurons alter their protein skeleton to reach for other cells. Disruptions to the cellular skeleton can harm memory formation. Tropomodulins (Tmods) are a family of proteins that contribute to the formation of the cellular skeleton in neurons. During seizures, strokes, and methamphetamine exposure and also in Down syndrome and epilepsy, the amounts of Tmods in the brain have been shown to be vastly altered. Understanding the role of Tmods in brain development will elucidate these conditions and may lead to treatments. Previous studies have shown that variation in Tmods' roles in neurite formation correlates with structural differences. The goal of this project is to determine the atomic structure (determinant in protein function) of Tmod2 for comparison with the known structure of Tmod1. This project will be conducted in collaboration with Dr. Fadel Samatey, an expert in protein structure at the Okinawa Institute of Science and Technology in Japan. A solved structure for Tmod2 will uncover details about Tmods' finely tuned role in brain development and disruption in disease states. Crystallization and X-ray Diffraction are techniques that will be used to determine protein structure. This project aims to screen for and optimize crystallization conditions for the leucine rich repeat (LRR) domain of Tmod2 and then determine its structure by X-ray Diffraction. This domain is important for localization of Tmods in muscle cells, thymosin binding and Tmod's actin nucleation ability. Comparison of Tmod structures will lead to residues for mutagenesis that will connect the structure of these proteins to their roles in neurite formation. This NSF EAPSI award is funded in collaboration with the Japan Society for the Promotion of Science.

大脑通过一组称为神经元的特殊细胞进行交流和形成记忆。这些细胞通过称为神经突的延伸形成连接。当神经元改变它们的蛋白质骨架以到达其他细胞时，就形成了神经突。细胞骨架的破坏会损害记忆的形成。原酸调节蛋白（Tmods）是一个有助于神经元细胞骨架形成的蛋白质家族。在癫痫发作、中风和甲基苯丙胺暴露期间，以及唐氏综合症和癫痫中，大脑中Tmods的数量已被证明发生了巨大变化。了解Tmods在大脑发育中的作用将阐明这些条件，并可能导致治疗。先前的研究表明，Tmods在神经突形成中的作用的变化与结构差异相关。该项目的目标是确定Tmod 2的原子结构（蛋白质功能的决定因素），以与Tmod 1的已知结构进行比较。该项目将与日本冲绳科学技术研究所蛋白质结构专家Fadel Samatey博士合作进行。Tmod2的解决结构将揭示Tmods在大脑发育和疾病状态中断中的微调作用的细节。结晶和X射线衍射是将用于确定蛋白质结构的技术。本项目旨在筛选和优化Tmod 2的富含亮氨酸重复（LRR）结构域的结晶条件，然后通过X射线衍射确定其结构。该结构域对于Tmod在肌细胞中的定位、胸腺素结合和Tmod的肌动蛋白成核能力是重要的。Tmod结构的比较将导致用于诱变的残基，其将这些蛋白质的结构与它们在神经突形成中的作用相连接。这个NSF EAPSI奖是与日本科学促进协会合作资助的。