Is S-palmitoylation the next phosphorylation? Research surrounding S-palmitoylation, the reversible post-translational modification, is about to explode thanks to novel detection techniques being utilised – get ahead of the game and find out its importance in neurodevelopment.

S-palmitoylation is the reversible attachment of a fatty acid to the cysteine residue of a target protein1. Between 25 and 40% of eukaryotic cellular proteins are membrane associated, whilst an even higher number of intracellular proteins can undergo modifications to localise them to the phospholipid bilayer and increase association with the membrane2. S-palmitoylation typically occurs as a follow-up to prenylation/myristoylation, which attaches a lipid to the protein to promote transient membrane attachments; S-palmitoylation subsequently inhibits protein dissociation from the membrane, as the palmitoylate group acts as a hydrophobic membrane anchor3. 4.

S-palmitoylation is considered to be especially vital in the central nervous system (CNS) – in fact, over 250 proteins expressed in neurones have been identified as S-palmitoylated proteins, and palmitic acid is the fatty acid in the highest concentration in the brain5,6. Examples of S-palmitoylated proteins or protein subunits in the CNS include α subunits of Na+ and β2a subunits of Ca2+ channels , serotonin 1B and 4A receptors, D1 and D2L dopamine receptors, α7 subunit of nicotinic and γ2 subunits of GABAA receptors, as well as various scaffolding proteins , GTPases, chaperones and myelin- associated proteins5,7. However, one notable S-palmitoylated neuronal protein is postsynaptic density-95, PSD-95.

The S-palmitoylation of the postsynaptic scaffolding protein PSD-95 influences synaptic strength and plasticity, due to its involvement in the regulation of postsynaptic glutamate expression. Furthermore, the dysregulation of PSD-95 S-palmitoylation is implicated in Huntington’s disease, whereby altered glutamate expression contributes to disease pathology.

To find out more on the importance of the S-palmitoylation of PSD-95, check out https://badrilla.com/project-landing. If you can spare a couple of minutes, please also fill out the short survey on the landing page – the results are anonymous and will help a final year dissertation project!

  1. Guan, X. & Fierke, C.A. 2011. Understanding Protein Palmitoylation: Biological Significance and Enzymology. Sci China Chem. [Online] 54(12): pp1888-1897. [Date Accessd: 21st February 2017]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/25419213
  2. Pei, Z., Xiao, Y., Meng, J., Hudmon, A. & Cummins, T. R. 2016. Cardiac sodium channel palitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation. Nature Communications. [Online]. 7(1): 12035. doi: 10.1038/ncomms12035. [Date Accessed: 21st February 2017]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27337590
  3. Yeste-Velasco, M., Linder, M.E., & Lu, Y-J. 2015. Protein S-palmitoylation and Cancer. Biochimica et Physica Acta. [Online]. 1856(1): pp107-120. [Date Accessed: 21st February 2017]. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26112306
  4. Greaves J. and Chamberlain L. H. 2011. DHHC palmitoyl transferases: substrate interactions and (patho)physiology. Trend in Biochemical Sciences. [Online]. 36(5):245–253. Date Accessed: 11th February 2017.] Available from: http://www.cell.com/trends/biochemical-sciences/fulltext/S0968-0004(11)00014-4
  5. Hayashi T., Rumbaugh G. and Huganir R. L. 2005. Differential regulation of AMPA receptor subunit trafficking by palmitoylation of two distinct sites. Neuron. [Online]. 47(5):709-23. [Date Accessed: 11th February 2017]. Available from: https://ncbi.nlm.nih.gov/pubmed/16129400
  6. Dalva M. B. 2009. Neuronal activity moves protein palmitoylation into the synapse. Journal of Cell Biology. [Online]. 186(1): 7–9. [Date Accessed: 11th February 2017]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712999/
  7. Kang R., Wan J., Arstikaitis P., Takahashi H., Huang K., Bailey A. O., Thompson J. X., Roth A. F., Drisdel R. C., Mastro R., Green W. N., John R. Yates J. R. 3rd, Davis N. G. and El-Husseini A. 2008. Neural Palmitoyl-Proteomics Reveals Dynamic Synaptic Palmitoylation. Nature. [Online]. 456(7224): 904–909. [Date Accessed:11th February 2017]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610860/#BX1

 

 

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