palmitoylation

{{short description|Attachment of a palmitoyl group (fatty acid) to a protein}}

Image:Palmitic acid.svg, pictured above) is added.]]

File:PalmitoylationAnkGc.jpg G to the plasma membrane. Right Close up. Palmityl residue in yellow.]]

File:Gephyrinc.jpg Controls Receptor Clustering and Plasticity of GABAergic Synapses]]

In molecular biology, palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (S-palmitoylation) and less frequently to serine and threonine (O-palmitoylation) residues of proteins, which are typically membrane proteins.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). The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their membrane association. Palmitoylation also appears to play a significant role in subcellular trafficking of proteins between membrane compartments,{{cite journal|vauthors=Rocks O, Peyker A, Kahms M, Verveer PJ, Koerner C, Lumbierres M, Kuhlmann J, Waldmann H, Wittinghofer A, Bastiaens PI | title=An acylation cycle regulates localization and activity of palmitoylated Ras isoforms | journal=Science | year=2005| volume=307 | issue= 5716 | pages=1746–1752 | pmid=15705808 | doi=10.1126/science.1105654| bibcode=2005Sci...307.1746R | s2cid=12408991 }} as well as in modulating protein–protein interactions.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

In contrast to prenylation and myristoylation, palmitoylation is usually reversible (because the bond between palmitic acid and protein is often a thioester bond). The reverse reaction in mammalian cells is catalyzed by acyl-protein thioesterases (APTs) in the cytosol and palmitoyl protein thioesterases in 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 hemagglutinin, a membrane glycoprotein used by influenza to attach to host cell receptors.{{cite encyclopedia | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7GG4-4CK7DHD-S&_rdoc=5&_hierId=42642&_refWorkId=141&_explode=42642&_alpha=I&_fmt=full&_orig=na&_docanchor=&_idxType=AR&view=c&_ct=10&_acct=C000011279&_version=1&_urlVersion=0&_userid=5399531&md5=607bbb1a7d18138457365550b9471eb5 | archive-url = https://archive.today/20120912120131/http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7GG4-4CK7DHD-S&_rdoc=5&_hierId=42642&_refWorkId=141&_explode=42642&_alpha=I&_fmt=full&_orig=na&_docanchor=&_idxType=AR&view=c&_ct=10&_acct=C000011279&_version=1&_urlVersion=0&_userid=5399531&md5=607bbb1a7d18138457365550b9471eb5 | url-status = dead | archive-date = 2012-09-12 | doi = 10.1006/rwvi.1999.0157 | encyclopedia=Encyclopedia of Virology | pages=830–836| year = 1999 | last1 = Palese | first1 = Peter |title = INFLUENZA VIRUSES (ORTHOMYXOVIRIDAE) | Molecular Biology| last2 = García-Sastre | first2 = Adolfo | isbn = 9780122270307 | url-access = subscription }} The palmitoylation cycles of a wide array of enzymes have been characterized in the past few years, including H-Ras, Gsα, the 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.{{cite journal|last=Wall|first=MA|author2=Coleman, DE |author3=Lee, E |author4=Iñiguez-Lluhi, JA |author5=Posner, BA |author6=Gilman, AG |author7= Sprang, SR |title=The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2.|journal=Cell|date=Dec 15, 1995|volume=83|issue=6|pages=1047–58|pmid=8521505|doi=10.1016/0092-8674(95)90220-1|doi-access=free}}

Mechanism

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.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 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.{{cite journal |last1=Li |first1=Y |last2=Qi |first2=B |title=Progress toward Understanding Protein S-acylation: Prospective in Plants. |journal=Frontiers in Plant Science |date=2017 |volume=8 |pages=346 |doi=10.3389/fpls.2017.00346 |pmid=28392791 |pmc=5364179|doi-access=free }}{{cite web |title=Proteolipids - proteins modified by covalent attachment to lipids - N-myristoylated, S-palmitoylated, prenylated proteins, ghrelin, hedgehog proteins |url=https://www.lipidmaps.org/resources/lipidweb/lipidweb_html/lipids/simple/protlip/index.htm |website=www.lipidmaps.org.co.uk |access-date=19 July 2021}}

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.{{cite journal |last1=Rana |first1=MS |last2=Lee |first2=CJ |last3=Banerjee |first3=A |title=The molecular mechanism of DHHC protein acyltransferases. |journal=Biochemical Society Transactions |date=28 February 2019 |volume=47 |issue=1 |pages=157–167 |doi=10.1042/BST20180429 |pmid=30559274|s2cid=56175691 }}

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.

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.{{cite journal | vauthors = Sanders SS, Martin DD, Butland SL, Lavallée-Adam M, Calzolari D, Kay C, Yates JR, Hayden MR | title = Curation of the Mammalian Palmitoylome Indicates a Pivotal Role for Palmitoylation in Diseases and Disorders of the Nervous System and Cancers | journal = PLOS Computational Biology | volume = 11 | issue = 8 | pages = e1004405 | date = August 2015 | pmid = 26275289 | pmc = 4537140 | doi = 10.1371/journal.pcbi.1004405 | bibcode = 2015PLSCB..11E4405S | doi-access = free }}

Biological function

=Substrate presentation=

Palmitoylation mediates the affinity of a protein for lipid rafts and facilitates the clustering of proteins.{{cite journal |last1=Levental |first1=I. |last2=Lingwood |first2=D. |last3=Grzybek |first3=M. |last4=Coskun |first4=U. |last5=Simons |first5=K. |title=Palmitoylation regulates raft affinity for the majority of integral raft proteins |journal=Proceedings of the National Academy of Sciences |date=3 December 2010 |volume=107 |issue=51 |pages=22050–22054 |doi=10.1073/pnas.1016184107|pmid=21131568 |pmc=3009825 |bibcode=2010PNAS..10722050L |doi-access=free }} 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.{{cite journal |last1=Petersen |first1=EN |last2=Chung |first2=HW |last3=Nayebosadri |first3=A |last4=Hansen |first4=SB |title=Kinetic disruption of lipid rafts is a mechanosensor for phospholipase D. |journal=Nature Communications |date=15 December 2016 |volume=7 |pages=13873 |doi=10.1038/ncomms13873 |pmid=27976674|pmc=5171650 |bibcode=2016NatCo...713873P }}{{cite journal |last1=Robinson |first1=CV |last2=Rohacs |first2=T |last3=Hansen |first3=SB |title=Tools for Understanding Nanoscale Lipid Regulation of Ion Channels. |journal=Trends in Biochemical Sciences |date=September 2019 |volume=44 |issue=9 |pages=795–806 |doi=10.1016/j.tibs.2019.04.001 |pmid=31060927|pmc=6729126 }}{{cite journal |last1=Petersen |first1=EN |last2=Pavel |first2=MA |last3=Wang |first3=H |last4=Hansen |first4=SB |title=Disruption of palmitate-mediated localization; a shared pathway of force and anesthetic activation of TREK-1 channels |journal= Biochimica et Biophysica Acta (BBA) - Biomembranes|volume=1862 |issue=1 |date=28 October 2019 |pages=183091 |doi=10.1016/j.bbamem.2019.183091 |pmid=31672538|pmc=6907892 }}

=General Anesthesia=

Palmitoylation is necessary for the inactivation of anesthesia, inducing potassium channels and the localization of GABA_AR 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.{{cite journal |last1=Pavel |first1=Mahmud Arif |last2=Petersen |first2=E. Nicholas |last3=Wang |first3=Hao |last4=Lerner |first4=Richard A. |last5=Hansen |first5=Scott B. |title=Studies on the mechanism of general anesthesia |journal=Proceedings of the National Academy of Sciences |date=16 June 2020 |volume=117 |issue=24 |pages=13757–13766 |doi=10.1073/pnas.2004259117|doi-access=free |pmid=32467161 |pmc=7306821 |bibcode=2020PNAS..11713757P }} 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 {{cite journal|last1=Greaves|first1=Jennifer|title=Differential palmitoylation regulates intracellular patterning of SNAP25|journal=Journal of Cell Science|date=March 2011|volume=124|issue=8|pages=1351–1360|doi=10.1242/jcs.079095|pmid=21429935|pmc=3065388}} and allows the SNARE complex to dissociate during vesicle fusion. This provides a role for palmitoylation in regulating neurotransmitter release."Molecular Mechanisms of Synaptogenesis." Edited by Alexander Dityatev and Alaa El-Husseini. Springer: New York, NY. 2006. pg. 72-75

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.{{cite journal |vauthors=Brigidi GS, Sun Y, Beccano-Kelly D, Pitman K, Jobasser M, Borgland SL, Milnerwood AJ, Bamji SX |title=Palmitoylation of [delta]-catenin by DHHC5 mediates activity-induced synapse plasticity |journal=Nature Neuroscience |date=January 23, 2014 |doi=10.1038/nn.3657 |pmid=24562000 |volume=17 |issue=4 |pages=522–532|pmc=5025286 }}

Palmitoylation of gephyrin has been reported to influence GABAergic synapses.{{cite journal | vauthors = Dejanovic B, Semtner M, Ebert S, Lamkemeyer T, Neuser F, Lüscher B, Meier JC, Schwarz G | title = Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses | journal = PLOS Biology | volume = 12 | issue = 7 | pages = e1001908 | date = July 2014 | pmid = 25025157 | pmc = 4099074 | doi = 10.1371/journal.pbio.1001908 | doi-access = free }}

References

External links

[http://csspalm.biocuckoo.org/ CSS-Palm - Palmitoylation Site Prediction with a Clustering and Scoring Strategy]
[https://web.archive.org/web/20140429215311/http://doc.aporc.org/wiki/CKSAAP-Palm CKSAAP-Palm]
[https://swisspalm.org Swisspalm - S-Palmitoylation database]

Category:Peripheral membrane proteins

Category:Post-translational modification