EAPSI: Regulation of Neuronal Communication by Protein Lipid Modifications

蛋白质脂化是一个调节分子分布的过程，对神经元间的空间和时间通讯至关重要。这项拟议的研究旨在探索zDHHC9-GCP16的作用，它可能是大脑脂化的主要调节因子之一。该项目将与Masaki Fukata博士（国家生理科学研究所，冈崎，爱知县，日本）合作完成，他是神经生物学领域的领导者，因为它与蛋白质脂化有关。这次合作为我们提供了利用细胞生物学中最先进的技术来了解神经元脂化的机会。这个项目的总体目标是在分子水平上增加对学习、记忆和运动功能的理解。棕榈酰化是在翻译后将16碳脂肪酸添加到底物的半胱氨酸残基上，这有助于促进膜的附着/分布。在神经元中，棕榈酰化可能通过PSD95、AMPAR、NMDAR、SNAP25和H-Ras等重要突触信号蛋白的时空组织，在维持突触形态和功能方面发挥着广泛的作用。这一过程由蛋白酰基转移酶（PATs）家族催化，Ras PAT zDHHC9-GCP16影响突触H-Ras的定位。然而，神经元中酶-底物特异性的机制尚不清楚。该项目旨在确定zDHHC9-GCP16在神经元中的亚细胞定位，因为在其他情况下，PAT定位到独特的神经元室是已知的特异性机制。为了确定zDHHC9-GCP16的其他神经元底物，将选择类似定位的候选底物子集，并确定zDHHC9-GCP16存在对底物定位的影响。由于zDHHC9-GCP16在大脑中高度表达，并且已知可以调节至少一种必需信号蛋白的分布，因此确定其在神经元中的作用将有助于更好地了解突触的时空组织。NSF EAPSI奖是与日本科学促进会合作资助的。

Protein lipidation is a process that regulates the distribution of molecules essential to neuron-neuron communication over space and time. The proposed research aims to explore the role of zDHHC9-GCP16, which is potentially one of the primary regulators of lipidation in the brain. This project will be done in collaboration with Dr. Masaki Fukata (National Institute of Physiological Sciences, Okazaki, Aichi, Japan), a leader in the field of neurobiology as it relates to protein lipidation. This collaboration affords us the opportunity to understand lipidation in the neuron using state-of-the-art techniques in cell biology. The overall aim of this project is to increase understanding of learning, memory, and motor function on a molecular level.Palmitoylation is the post-translational addition of a 16-carbon fatty acid to a cysteine residue of a substrate, which serves to facilitate membrane attachment/distribution. In the neuron, palmitoylation may serve a broad role in maintenance of synapse morphology and function through spatiotemporal organization of essential synaptic signaling proteins such as PSD95, AMPAR, NMDAR, SNAP25, and H-Ras. This process is catalyzed by a family of protein acyltransferases (PATs), and the Ras PAT zDHHC9-GCP16 affects the localization of synaptic H-Ras. However, the mechanism of enzyme-substrate specificity in the neuron is poorly understood. This project aims to determine the subcellular localization of zDHHC9-GCP16 in the neuron, as PAT localization to unique neuronal compartments is a known mechanism of specificity in other cases. To determine additional neuronal substrates of zDHHC9-GCP16, a subset of similarly localized candidate substrates will be selected and the effect of zDHHC9-GCP16 presence on substrate localization will be determined. As zDHHC9-GCP16 is highly expressed in the brain and is known to regulate distribution of at least one essential signaling protein, establishing its role in the neuron will lead to greater understanding of the spatiotemporal organization of the synapse. This NSF EAPSI award is funded in collaboration with the Japan Society for the Promotion of Science.