Palmitoylation

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Not to be confused with Palmitoleoylation.
In palmitoylation, a palmitoyl group (derived from palmitic acid, pictured above) is added.
Palmitoylation of a cysteine residue
Left Palmitoylation (red) anchors Ankyrin G to the plasma membrane. Right Close up. Palmityl residue in yellow.
Palmitoylation of Gephyrin Controls Receptor Clustering and Plasticity of GABAergic Synapses[1]

Palmitoylation is the covalent attachment of

lysosomes
. Because palmitoylation is a dynamic, post-translational process, it is believed to be employed by the cell to alter the subcellular localization, protein–protein interactions, or binding capacities of a protein.

An example of a protein that undergoes palmitoylation is

β2-adrenergic receptor, and endothelial nitric oxide synthase (eNOS). In signal transduction via G protein, palmitoylation of the α subunit, prenylation of the γ subunit, and myristoylation is involved in tethering the G protein to the inner surface of the plasma membrane so that the G protein can interact with its receptor.[6]

Mechanism

S-palmitoylation is generally done by proteins with the

oleate (C18:1) are also frequently accepted, more so in plant and viral proteins, making S-acylation a more useful name.[8][9]

Several structures of the DHHC domain have been determined using

ping-pong mechanism, where the cysteine attacks the acyl-CoA to form an S-acylated DHHC, and then the acyl group is transferred to the substrate. DHHR enzymes exist, and it (as well as some DHHC enzymes) may use a ternary complex mechanism instead.[10]

An inhibitor of S-palmitoylation by DHHC is 2-Bromopalmitate (2-BP). 2-BP is a nonspecific inhibitor that also halts many other lipid-processing enzymes.[7]

The palmitoylome

A

mammalian proteins that are palmitoylated. The highest associations of the palmitoylome are with cancers and disorders of the nervous system. Approximately 40% of synaptic proteins were found in the palmitoylome.[11]

Biological function

Substrate presentation

Palmitoylation mediates the affinity of a protein for

lipid rafts and facilitates the clustering of proteins.[12] The clustering can increase the proximity of two molecules. Alternatively, clustering can sequester a protein away from a substrate. For example, palmitoylation of phospholipase D (PLD) sequesters the enzyme away from its substrate phosphatidylcholine. When cholesterol levels decrease or PIP2 levels increase the palmitate mediated localization is disrupted, the enzyme trafficks to PIP2 where it encounters its substrate and is active by substrate presentation.[13][14][15]

General Anesthesia

Palmitoylation is necessary for the inactivation of anesthesia inducing potassium channels and the localization of GABAAR in synapses. Anesthetics compete with palmitate in ordered lipids and this release gives rise to a component of membrane-mediated anesthesia. For example the anesthesia channel TREK-1 is activated by anesthetic displacement from GM1 lipids.[16] The palmitoylation site is specific for palmitate over prenylation, however, the anesthetics appear to compete non-specifically. This non-selective competition of anesthetic with palmitate likely gives rise to rise to the Myer-Overton correlation.

Synapse formation

Scientists have appreciated the significance of attaching long hydrophobic chains to specific proteins in cell signaling pathways. A good example of its significance is in the clustering of proteins in the synapse. A major mediator of protein clustering in the synapse is the postsynaptic density (95kD) protein

SNARE complex to dissociate during vesicle fusion. This provides a role for palmitoylation in regulating neurotransmitter release.[18]

Palmitoylation of

delta catenin seems to coordinate activity-dependent changes in synaptic adhesion molecules, synapse structure, and receptor localizations that are involved in memory formation.[19]

Palmitoylation of gephyrin has been reported to influence GABAergic synapses.[1]

See also

References

  1. ^
    PMID 25025157
    .
  2. ^ Linder, M.E., "Reversible modification of proteins with thioester-linked fatty acids," Protein Lipidation, F. Tamanoi and D.S. Sigman, eds., pp. 215-40 (San Diego, CA: Academic Press, 2000).
  3. S2CID 12408991
    .
  4. ^ Basu, J., "Protein palmitoylation and dynamic modulation of protein function," Current Science, Vol. 87, No. 2, pp. 212-17 (25 July 2004), http://www.ias.ac.in/currsci/jul252004/contents.htm
  5. ISBN 9780122270307. Archived from the original
    on 2012-09-12.
  6. PMID 8521505
    .
  7. ^ a b Lanyon-Hogg, T., Faronato, M., Serwa, R. A., & Tate, E. W. (2017). Dynamic Protein Acylation: New Substrates, Mechanisms, and Drug Targets. Trends in Biochemical Sciences, 42(7), 566–581. doi:10.1016/j.tibs.2017.04.004
  8. PMID 28392791
    .
  9. ^ "Proteolipids - proteins modified by covalent attachment to lipids - N-myristoylated, S-palmitoylated, prenylated proteins, ghrelin, hedgehog proteins". www.lipidmaps.org.co.uk. Retrieved 19 July 2021.
  10. S2CID 56175691
    .
  11. PMID 26275289
    .
  12. PMID 21131568
    .
  13. PMID 27976674
    .
  14. PMID 31060927
    .
  15. PMID 31672538
    .
  16. PMC 7306821
    .
  17. PMID 21429935
    .
  18. ^ "Molecular Mechanisms of Synaptogenesis." Edited by Alexander Dityatev and Alaa El-Husseini. Springer: New York, NY. 2006. pg. 72-75
  19. PMID 24562000
    .

Further reading

External links
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