EAPSI: Regulation of Neuronal Communication by Protein Lipid Modifications

蛋白质脂质化是一个调节神经元-神经元通讯所必需的分子在空间和时间上的分布的过程。这项研究旨在探索zDHHC 9-GCP 16的作用，它可能是大脑中脂化的主要调节因子之一。该项目将与Masaki Akuata博士（日本爱知县冈崎市国立生理科学研究所）合作完成，Masaki Akuata博士是神经生物学领域的领导者，因为它与蛋白质脂化有关。这次合作使我们有机会使用细胞生物学中最先进的技术来了解神经元的脂化。棕榈酰化是一种在翻译后将16个碳的脂肪酸加到底物的半胱氨酸残基上的过程，它有助于促进膜的附着/分布。在神经元中，棕榈酰化可以通过基本突触信号传导蛋白如PSD 95、AMPAR、NMDAR、SNAP 25和H-Ras的时空组织在维持突触形态和功能中发挥广泛作用。该过程由蛋白酰基转移酶（PAT）家族催化，并且Ras PAT zDHHC 9-GCP 16影响突触H-Ras的定位。然而，神经元中酶-底物特异性的机制知之甚少。该项目旨在确定zDHHC 9-GCP 16在神经元中的亚细胞定位，因为PAT定位于独特的神经元区室是其他情况下的特异性的已知机制。为了确定zDHHC 9-GCP 16的另外的神经元底物，将选择类似定位的候选底物的子集，并将确定zDHHC 9-GCP 16存在对底物定位的影响。由于zDHHC 9-GCP 16在大脑中高度表达，并且已知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导致对突触时空组织的更好理解。这个NSF EAPSI奖是与日本科学促进协会合作资助的。

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.