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Protein palmitoylation in neuronal development and synaptic plasticity

Nature Reviews Neuroscience volume 11, pages 161–175 (2010)Cite this article

Subjects

Key Points

  • Post-translational modification, including protein phosphorylation and lipid modification, provides proteins with additional function and regulatory control beyond genomic information, allowing cells to maintain homeostasis and respond to extracellular signals.

  • Protein palmitoylation —the common lipid modification with the lipid palmitate — regulates protein trafficking and function, as well as signalling. Palmitoylation modifies numerous proteins including synaptic scaffolding, signalling and cytoskeletal proteins to target them to specialized membrane microdomains.

  • Palmitoylation is a unique post-translational modification in that it is reversible and dynamically regulated by specific extracellular signals. The reversible nature of protein palmitoylation allows proteins to shuttle between intracellular compartments. For example, protein palmitoylation regulates the Golgi–plasma membrane shuttling of the small GTPase HRAS and the G protein subunit Gα.

  • Proteome analyses have identified numerous new palmitoyl substrates in the brain, such as brain-specific CDC42 and NMDA (N-methyl-D-aspartate) receptor subunits.

  • The finely tuned protein targeting by palmitoylation aids neuronal development and synaptic plasticity. However, the molecular mechanisms of protein palmitoylation have long been elusive.

  • The large family of DHHC-type (Asp-His-His-Cys) palmitoyl-acyltransferases, conserved from plants to mammals, has recently been identified. Systematic screening methods have revealed various enzyme–substrate pairs.

  • The DHHC-type palmitoylating enzymes are classified into several subfamilies and differently regulated in polarized neurons. For example, DHHC3 stably localizes at the Golgi apparatus, whereas dendritically localized DHHC2 moves to the postsynaptic density in an activity-sensitive manner and mediates palmitoylation of postsynaptic density protein 95 (PSD95). This increases the accumulation of synaptic PSD95 and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors upon activity blockade, contributing to homeostatic plasticity.

  • The next step in this field of research is to identify the family of enzymes that mediate removal of protein palmitate — the depalmitoylating enzymes. It will also be important to analyse transgenic animals that have mutations in DHHC-type palmitoylating enzymes.

Abstract

Protein palmitoylation, a classical and common lipid modification, regulates diverse aspects of neuronal protein trafficking and function. The reversible nature of palmitoylation provides a potential general mechanism for protein shuttling between intracellular compartments. The recent discovery of palmitoylating enzymes — a large DHHC (Asp-His-His-Cys) protein family — and the development of new proteomic and imaging methods have accelerated palmitoylation analysis. It is becoming clear that individual DHHC enzymes generate and maintain the specialized compartmentalization of substrates in polarized neurons. Here, we discuss the regulatory mechanisms for dynamic protein palmitoylation and the emerging roles of protein palmitoylation in various aspects of pathophysiology, including neuronal development and synaptic plasticity.

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Figure 1: Roles of palmitoylation in neurons.
Figure 2: Palmitoylation–depalmitoylation cycles mediate inter-compartment shuttling of proteins.
Figure 3: DHHC-type palmitoylating enzyme family and identified enzyme–substrate pairs.
Figure 4: Differential regulation of DHHC enzymes in neurons.

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Acknowledgements

We thank J. Noritake, R. Tsutsumi, T. Iwanaga and N. Yokoi in our laboratory for preparing the manuscript, and D. S. Bredt (Eli Lilly and Company) and M. Nishijima (National Institute of Health Sciences and PRESTO, JST) for encouragement. We apologize to researchers whose work could not be cited owing to space constraints. The original work by the authors was supported by grants from Human Frontier Science Program (CDA0015-07 to Y.F. and RGY0059-06 to M.F.), MEXT (21680029 to Y.F. and 20670005, 20022043 and 20054022 to M.F.) and PRESTO (Y.F. and M.F.).

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  1. Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, Okazaki, 444-8787, Aichi, Japan

    Yuko Fukata & Masaki Fukata

  2. PRESTO, Japan Science and Technology Agency, Chiyoda, 102-0075, Tokyo, Japan

    Yuko Fukata

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Glossary

Myristoylation

The co-translational attachment of 14-carbon myristic acid to an amino-terminal glycine residue through a stable amide linkage, catalysed by N-myristoyltransferase.

Prenylation

The post-translational attachment of a prenyl group — 15-carbon farnesyl (farnesylation) or 20-carbon geranylgeranyl group (geranylgeranylation) — to a specific cysteine residue in the carboxy-terminal motif CaaX (in which C is a prenyl cysteine and a and X represent aliphatic and any residues, respectively).

Lipid raft

A submicrodomain of the plasma membrane that is enriched in sphingolipids and cholesterol, and is thought to serve as a signalling platform.

Proteomics

Large-scale comprehensive description of protein expression and protein–protein interactions, carried out by mass spectrometry and accompanied by a search of protein databases.

Multidimensional protein identification technology

(MudPIT). A protein identification method based on improved peptide separation of complex samples using multidimensional liquid chromatography coupled to tandem mass spectrometry.

Copper (I)-catalysed azide–alkyne cycloaddition (click) chemistry

Chemical reactions that use bio-orthogonal moieties to label a molecule of interest, involving a copper-catalysed triazole formation from an azide and an alkyne.

Electroretinogram

A recording of the electrical responses of the light-sensitive cells in the eye.

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Fukata, Y., Fukata, M. Protein palmitoylation in neuronal development and synaptic plasticity. Nat Rev Neurosci 11, 161–175 (2010). https://doi.org/10.1038/nrn2788

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