Biology:Palmitoylation

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Short description: Post-translational modification

Template:PTM infobox Protein palmitoylation refers to the post-translational modification in which palmitate is covalently attached to an amino acid residue on a target protein via palmitoyl acyltransferases.[1] Palmitoylation itself refers to the overall class of post-translational modifications involving palmitate; however, these reactions are further classified by the individual amino acid residue for which they occur (ie., S-palmitoylation, N-palmitoylation, O-palmitoylation).[1]

Protein palmitoylation relies upon the intracellular availability of the donor molecule palmitoyl-CoA, which is synthesized in the cytosol of the cell. As a fatty acylation reaction, protein palmitoylation is classified as both an acylation and a lipidation post-translational modification.[1]

Notably, the reversibility of protein palmitoylation is determined by the amino acid residue on which the modification occurs.[2] O- and N-palmitoylation are stable, irreversible modifications comparable to that of N-myristoylation.[2] However, S-palmitoylation is a highly dynamic reversible modification, in which the reverse reaction is catalyzed by palmitoyl-protein thioesterases (PPTs).[2]

Palmitoylation is known to enhance the hydrophobicity of substrate proteins and thereby allows soluble proteins to associate with cellular membranes.[2][3] Palmitoylation also plays a significant role in regulating the stability and subcellular trafficking of proteins between membrane compartments, and is known to modulate protein–protein interactions.[1][3]

Palmitoylation has been reported for both histone and non-histone protein substrates, and thus represents a distinct epigenetic regulatory mechanism with various implications in health and disease.[4][5] Recent studies have unveiled the critical role of palmitoylation in mediating a wide range of physiological processes, including neurotransmission and immune responses.[6][7]

Palmitoylation is known to contribute to several significant diseases, including Huntington's diseaseand various cancers.[8][9] To date, palmitoylation is known to modify as many as 6,000 protein substrates,[10] including a large body of immunity-associated proteins,[2] metabolic transporters,[11] and synaptic proteins.[12]

Mechanism

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[13]

S-palmitoylation is generally done by proteins with the DHHC domain. Exceptions exist in non-enzymatic reactions. Acyl-protein thioesterase (APT) catalyses the reverse reaction.[14] Other acyl groups such as stearate (C18:0) or oleate (C18:1) are also frequently accepted, more so in plant and viral proteins, making S-acylation a more useful name.[15][16]

Several structures of the DHHC domain have been determined using X-ray crystallography. It contains a linearly-arranged catalytic triad of Asp153, His154, and Cys156. It runs on a 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.[17]

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.[14]

The palmitoylome

A meta-analysis of 15 studies produced a compendium of approximately 2,000 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.[18]

Biological function

Substrate presentation

Palmitoylation mediates the affinity of a protein for lipid rafts and facilitates the clustering of proteins.[19] 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 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.[20][21][22]

General Anesthesia

Palmitoylation is necessary for the inactivation of anesthesia, inducing potassium channels and the localization of GABAA receptors in synapses. Anesthetics compete with palmitate in ordered lipids and this release gives rise to a component of membrane-mediated anesthesia. For example, channel TREK-1 is activated by anesthetic displacement from GM1 lipids.[23] 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 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 PSD-95. When this protein is palmitoylated it is restricted to the membrane. This restriction to the membrane allows it to bind to and cluster ion channels in the postsynaptic membrane. Also, in the presynaptic neuron, palmitoylation of SNAP-25 directs it to partition in the cell membrane [24] and allows the SNARE complex to dissociate during vesicle fusion. This provides a role for palmitoylation in regulating neurotransmitter release.[25]

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.[26]

Palmitoylation of gephyrin has been reported to influence GABAergic synapses.[13]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 Li, Weini; Shen, Jie; Zhuang, Aojia; Wang, Ruiheng; Li, Quanqi; Rabata, Anas; Zhang, Yanan; Cao, DuoYao (2025). "Palmitoylation: an emerging therapeutic target bridging physiology and disease". Cellular & Molecular Biology Letters 30 (1): 98. doi:10.1186/s11658-025-00776-w. ISSN 1689-1392. PMID 40817227. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Zhang, Yuqi; Qin, Ziran; Sun, Wenhuan; Chu, Feng; Zhou, Fangfang (2021). "Function of Protein S-Palmitoylation in Immunity and Immune-Related Diseases" (in English). Frontiers in Immunology 12. doi:10.3389/fimmu.2021.661202. ISSN 1664-3224. PMID 34557182. 
  3. ↑ 3.0 3.1 Linder, Maurine E.; Deschenes, Robert J. (2007). "Palmitoylation: policing protein stability and traffic" (in en). Nature Reviews Molecular Cell Biology 8 (1): 74–84. doi:10.1038/nrm2084. ISSN 1471-0080. PMID 17183362. Bibcode: 2007NRMCB...8...74L. https://www.nature.com/articles/nrm2084. 
  4. ↑ Zheng, Xiyuan; Wu, Xinying; Wang, Lei; Ouyang, Haohong; Damira, Yeltokova; Peng, Bin; Xu, Xingzhi (2025). "S-palmitoylation: An oily modification guarding genome stability". DNA Repair 153. doi:10.1016/j.dnarep.2025.103883. ISSN 1568-7856. PMID 40815872. 
  5. ↑ Li, Jiaoyang; Xia, Zhizhou; Jiao, Bo; Li, Zhitong; Li, Donghe; Xu, Pengfei; Huang, Yi; Nie, Jiawei et al. (2025). "Palmitoyltransferase ZDHHC19 regulates histone-to-protamine exchange during spermiogenesis in mice". Science Advances 11 (42). doi:10.1126/sciadv.adv5189. PMID 41105761. Bibcode: 2025SciA...11.5189L. 
  6. ↑ Naumenko, Vladimir S.; Ponimaskin, Evgeni (2018). "Palmitoylation as a Functional Regulator of Neurotransmitter Receptors". Neural Plasticity 2018. doi:10.1155/2018/5701348. ISSN 1687-5443. PMID 29849559. 
  7. ↑ Zhang, Yuqi; Qin, Ziran; Sun, Wenhuan; Chu, Feng; Zhou, Fangfang (2021). "Function of Protein S-Palmitoylation in Immunity and Immune-Related Diseases". Frontiers in Immunology 12. doi:10.3389/fimmu.2021.661202. ISSN 1664-3224. PMID 34557182. 
  8. ↑ Wlodarczyk, Jakub; Bhattacharyya, Raja; Dore, Kim; Ho, Gary P. H.; Martin, Dale D. O.; Mejias, Rebeca; Hochrainer, Karin (2024). "Altered Protein Palmitoylation as Disease Mechanism in Neurodegenerative Disorders". The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 44 (40): e1225242024. doi:10.1523/JNEUROSCI.1225-24.2024. ISSN 1529-2401. PMID 39358031. 
  9. ↑ Zhou, Binhui; Hao, Qianyun; Liang, Yinming; Kong, Eryan (2023). "Protein palmitoylation in cancer: molecular functions and therapeutic potential". Molecular Oncology 17 (1): 3–26. doi:10.1002/1878-0261.13308. ISSN 1878-0261. PMID 36018061. 
  10. ↑ Mondal, T. et al. (2025). In vitro reconstitution reveals substrate selectivity of protein S-acyltransferases. Journal of Biol. Chem. 301(4): e108406. https://doi.org/10.1016/j.jbc.2025.108406
  11. ↑ Villanueva, Cecilia E.; Hagenbuch, Bruno (2023). "Palmitoylation of solute carriers". Biochemical Pharmacology 215. doi:10.1016/j.bcp.2023.115695. ISSN 1873-2968. PMID 37481134. 
  12. ↑ Peng, Jiaying; Liang, Danchan; Zhang, Zhonghao (2024). "Palmitoylation of synaptic proteins: roles in functional regulation and pathogenesis of neurodegenerative diseases". Cellular & Molecular Biology Letters 29 (1): 108. doi:10.1186/s11658-024-00625-2. ISSN 1689-1392. PMID 39127627. 
  13. ↑ 13.0 13.1 "Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses". PLOS Biology 12 (7). July 2014. doi:10.1371/journal.pbio.1001908. PMID 25025157. 
  14. ↑ 14.0 14.1 Lanyon-Hogg, Thomas; Faronato, Monica; Serwa, Remigiusz A.; Tate, Edward 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. PMID 28602500. 
  15. ↑ Li, Y; Qi, B (2017). "Progress toward Understanding Protein S-acylation: Prospective in Plants.". Frontiers in Plant Science 8: 346. doi:10.3389/fpls.2017.00346. PMID 28392791. Bibcode: 2017FrPS....8..346L. 
  16. ↑ "Proteolipids - proteins modified by covalent attachment to lipids - N-myristoylated, S-palmitoylated, prenylated proteins, ghrelin, hedgehog proteins". https://www.lipidmaps.org/resources/lipidweb/lipidweb_html/lipids/simple/protlip/index.htm. 
  17. ↑ Rana, MS; Lee, CJ; Banerjee, A (28 February 2019). "The molecular mechanism of DHHC protein acyltransferases.". Biochemical Society Transactions 47 (1): 157–167. doi:10.1042/BST20180429. PMID 30559274. 
  18. ↑ "Curation of the Mammalian Palmitoylome Indicates a Pivotal Role for Palmitoylation in Diseases and Disorders of the Nervous System and Cancers". PLOS Computational Biology 11 (8). August 2015. doi:10.1371/journal.pcbi.1004405. PMID 26275289. Bibcode: 2015PLSCB..11E4405S. 
  19. ↑ Levental, I.; Lingwood, D.; Grzybek, M.; Coskun, U.; Simons, K. (3 December 2010). "Palmitoylation regulates raft affinity for the majority of integral raft proteins". Proceedings of the National Academy of Sciences 107 (51): 22050–22054. doi:10.1073/pnas.1016184107. PMID 21131568. Bibcode: 2010PNAS..10722050L. 
  20. ↑ Petersen, EN; Chung, HW; Nayebosadri, A; Hansen, SB (15 December 2016). "Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D.". Nature Communications 7. doi:10.1038/ncomms13873. PMID 27976674. Bibcode: 2016NatCo...713873P. 
  21. ↑ Robinson, CV; Rohacs, T; Hansen, SB (September 2019). "Tools for Understanding Nanoscale Lipid Regulation of Ion Channels.". Trends in Biochemical Sciences 44 (9): 795–806. doi:10.1016/j.tibs.2019.04.001. PMID 31060927. 
  22. ↑ Petersen, EN; Pavel, MA; Wang, H; Hansen, SB (28 October 2019). "Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels". Biochimica et Biophysica Acta (BBA) - Biomembranes 1862 (1). doi:10.1016/j.bbamem.2019.183091. PMID 31672538. 
  23. ↑ Pavel, Mahmud Arif; Petersen, E. Nicholas; Wang, Hao; Lerner, Richard A.; Hansen, Scott B. (16 June 2020). "Studies on the mechanism of general anesthesia". Proceedings of the National Academy of Sciences 117 (24): 13757–13766. doi:10.1073/pnas.2004259117. PMID 32467161. Bibcode: 2020PNAS..11713757P. 
  24. ↑ Greaves, Jennifer (March 2011). "Differential palmitoylation regulates intracellular patterning of SNAP25". Journal of Cell Science 124 (8): 1351–1360. doi:10.1242/jcs.079095. PMID 21429935. 
  25. ↑ "Molecular Mechanisms of Synaptogenesis." Edited by Alexander Dityatev and Alaa El-Husseini. Springer: New York, NY. 2006. pg. 72-75
  26. ↑ "Palmitoylation of [delta-catenin by DHHC5 mediates activity-induced synapse plasticity"]. Nature Neuroscience 17 (4): 522–532. January 23, 2014. doi:10.1038/nn.3657. PMID 24562000. 

Further reading



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