Neural palmitoyl-proteomics reveals dynamic synaptic palmitoylation

Palmitoylation regulates diverse aspects of neuronal protein trafficking and function. Here a global characterization of rat neural palmitoyl-proteomes identifies most of the known neural palmitoyl proteins—68 in total, plus more than 200 new palmitoyl-protein candidates, with further testing confirming palmitoylation for 21 of these candidates. The new palmitoyl proteins include neurotransmitter receptors, transporters, adhesion molecules, scaffolding proteins, as well as SNAREs and other vesicular trafficking proteins. Of particular interest is the finding of palmitoylation for a brain-specific Cdc42 splice variant. The palmitoylated Cdc42 isoform (Cdc42-palm) differs from the canonical, prenylated form (Cdc42-prenyl), both with regard to localization and function: Cdc42-palm concentrates in dendritic spines and has a special role in inducing these post-synaptic structures. Furthermore, assessing palmitoylation dynamics in drug-induced activity models identifies rapidly induced changes for Cdc42 as well as for other synaptic palmitoyl proteins, suggesting that palmitoylation may participate broadly in the activity-driven changes that shape synapse morphology and function. Palmitoylation, the addition of the lipid palmitate to proteins, plays an important role in modulating neuronal protein trafficking and function. A new proteomics study identifies palmitoylation as a key modifiable signal on many synapse-enriched proteins that contribute to activity-driven changes in synapse morphology and function. A large population of proteins — dubbed the neuronal 'palmitoyl-proteome' — is reversibly palmitoylated in response to neuronal activity. In particular, the study reveals a new, brain-specific isoform of the small GTPase Cdc42, whose unexpected palmitoylation specifically affects dendritic spine morphogenesis in response to neuronal activity. A proteomics study unveils a large collection of proteins that get reversibly palmitoylated in response to neuronal activity — the neuronal palmitoyl-proteome. In particular, this study focuses on the discovery of a brain-specific isoform of the small GTPase Cdc42, whose unexpected palmitoylation specifically affects dendritic spine morphogenesis in response to neuronal activity. These findings identify palmitoylation as a key modifiable signal on many synapse-enriched proteins that contribute to activity-driven changes in synapse morphology and function.