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  • Review Article
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Protein palmitoylation: a regulator of neuronal development and function

Nature Reviews Neuroscience volume 3, pages 791–802 (2002)Cite this article

Key Points

  • Palmitate is a 16-carbon saturated fatty acid that is attached to proteins post-translationally. This modification, which is called palmitoylation, increases protein hydrophobicity and facilitates protein interactions with lipid bilayers, and it can influence protein sorting and function.

  • The thioester bond that links protein to palmitate is labile and reversible, and specific physiological stimuli dynamically alter protein palmitoylation levels, providing an important mechanism for regulating cell development and signalling.

  • Recent work has shown that palmitoylation is important for the regulation of neuronal development and synaptic functions. It has been implicated in processes that include protein sorting, axonal development, presynaptic signalling, G-protein signalling, ion channel clustering and postsynaptic plasticity.

  • Rhodopsin was one of the first neuronal proteins to be found to contain covalently attached palmitate, and many others have since been identified. These include several G-protein-coupled receptors (GPCRs), growth-associated protein 43 (GAP43) and postsynaptic density protein 95 (PSD95).

  • The enzymes that mediate the palmitoylation of cellular proteins remain largely unknown, and non-enzymatic palmitoylation of certain protein cysteines has been observed in vitro. However, recent studies have identified the acyl-transferase that palmitoylates the hedgehog family of secreted glycoproteins, which can affect the development of neurons.

  • No common consensus sequence for palmitoylation has been identified, but some patterns have emerged. For example, for transmembrane proteins such as GPCRs, synaptotagmin and synaptobrevin, palmitoylation often occurs at cytosolic cysteine residues that are adjacent to the final transmembrane domain.

  • Further understanding of the roles of protein palmitoylation will require a more comprehensive identification of proteins that contain this modification. It will also be important to identify the family of enzymes that mediate the addition and removal of protein palmitate.

Abstract

Palmitoylation — the post-translational modification of proteins with the lipid palmitate — has emerged as an important mechanism for regulating protein trafficking and function. Classic studies showed that palmitoylation targets many signalling enzymes to specialized lipid microdomains on the cytosolic face of the plasma membrane, thereby directing their integration into specific transduction pathways. More recent work shows that palmitate reversibly modifies numerous classes of neuronal proteins, including neurotransmitter receptors, synaptic scaffolding proteins and secreted signalling molecules. This review highlights recent evidence that protein palmitoylation regulates trafficking and signalling pathways that are important for brain development and synaptic transmission.

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Figure 1: Palmitoylation-regulated protein sorting.
Figure 2: Dynamic palmitate turnover regulates signalling by GPCR pathways.
Figure 3: Palmitoylation of proteins regulates synaptic transmission.
Figure 4: Dynamic protein palmitoylation regulates clustering of AMPA receptors at the synapse.

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Acknowledgements

The authors thank L. Levy for help in preparing this manuscript. This work was supported by grants to A.E.E. from the Canadian Institutes of Health Research, the Michael Smith Foundation for Health Research and the National Alliance for Research on Schizophrenia and Depression, and by grants to D.S.B. from the National Institutes of Health, the Christopher Reeves Paralysis Foundation, the Human Frontier Research Program and the American Heart Association.

Author information

Authors and Affiliations

  1. Department of Psychiatry and the Brain Research Centre, Kinsmen Laboratory, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

    Alaa El-Din El-Husseini

  2. Department of Physiology, University of California at San Francisco School of Medicine, 513 Parnassus Avenue, San Francisco, 94143-0444, California, USA

    David S. Bredt

Authors
  1. Alaa El-Din El-Husseini
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Correspondence to David S. Bredt.

Related links

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DATABASES

LocusLink

ACBP

α2A-adrenoceptor

β2-adrenoceptor

AKAP18

AMPA receptors

APT

β-arrestin

calcium channel α1-subunit

calcium channel α2δ-subunit

calcium channel β-subunit

calmodulin

cysteine-string protein

Fyn

GAD65

GAP43

GluR6

GRIP

GRK

H-Ras

KChIPs

mGluR4

NCAM140

NMDA receptors

NOS

palmitoyl-transferase

paralemmin

patched

PPT1

PSD93

PSD95

RGS

RhoB

rhodopsin

SAP102

SAP97

Shh

Ski

α-SNAP

SNAP25

sodium channel α-subunit

Src

stargazin

synaptobrevin

synaptotagmin

Tc10

Thy-1

VAMP

OMIM

infantile neuronal ceroid lipofuscinosis

<i>Saccharomyces</i> Genome Database

ERF2

Ras

FURTHER INFORMATION

Encyclopedia of Life Sciences

G protein-coupled receptors

G proteins

regulation by covalent modification

Glossary

PARACRINE

A mechanism of signalling between cells that relies on the diffusion of signalling molecules through the intercellular spaces.

HETEROMERIC

Formed by the assembly of two or more different subunits.

PEROXISOME

A cellular microbody that contains enzymes that generate or metabolize hydrogen peroxide. In mammals, they have been identified in liver and kidney cells.

PULSE–CHASE EXPERIMENTS

Experiments in which the addition of a radioactive amino acid (pulse) is followed by non-labelled amino acid (chase), and the production of radioactive proteins from the amino-acid precursors is monitored.

GPI

Glycosyl phosphatidylinositol. A post-translational modification, the function of which is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C-6 hydroxyl of the inositol, and is attached to the protein through an ethanolamine phosphate moiety.

SPINES

Specialized regions of the dendrite that receive synaptic inputs from other neurons.

SNARE PROTEINS

A family of membrane-tethered coiled-coil proteins that are required for membrane fusion in exocytosis (such as during neurotransmitter release) and other membrane transport events. When trans-SNARE complexes are formed between vesicle SNAREs and target-membrane SNAREs, they pull the two membranes close together, presumably causing them to fuse.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. They can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs large, zona occludens 1).

METABOTROPIC

A term that describes a receptor that exerts its effects through enzyme activation.

ALTERNATIVE SPLICING

During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing allows the production of different messages from the same DNA molecule.

SH DOMAINS

Src-homology domains are involved in interactions with phosphorylated tyrosine residues on other proteins (SH2 domains) or with proline-rich sections of other proteins (SH3 domains).

CHROMAFFIN CELLS

Cells of the adrenal gland that store and secrete catecholamines. The term 'chromaffin' reflects the ability of chromium salts to stain them.

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El-Husseini, AD., Bredt, D. Protein palmitoylation: a regulator of neuronal development and function. Nat Rev Neurosci 3, 791–802 (2002). https://doi.org/10.1038/nrn940

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