Protein palmitoylation, or the reversible addition of the fatty acid, palmitate, onto substrate proteins, can impact the structure and stability of proteins as well as regulate protein-protein interactions and the trafficking and localization of proteins to cell membranes. This posttranslational modification is mediated by palmitoyl-acyltransferases, consisting of a family of 23 zDHHC proteins in mammals. This review focuses on the subcellular distribution of zDHHC proteins within the neuron and the regulation of zDHHC trafficking and function by synaptic activity. We review recent studies identifying actin binding proteins, cell adhesion molecules and synaptic scaffolding proteins as targets of palmitoylation, and examine the implications of activity-mediated palmitoylation in the establishment and plasticity of neuronal connections.
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