EAPSI: Regulation of Neuronal Communication by Protein Lipid Modifications

Reddy Krishna, Tampa FL

Investigators

Abstract

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.