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Palmitoylation

February 15, 2024

Not to be confused with Palmitoleoylation.

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.[2] 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,[3] as well as in modulating protein–protein interactions.[4] 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.

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]

An example of a protein that undergoes palmitoylation is hemagglutinin, a membrane glycoprotein used by influenza to attach to host cell receptors.[5] 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.[6]

Mechanism edit

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.[7] 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.[8][9]

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.[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 edit

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.[11]

Biological function edit

Substrate presentation edit

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 edit

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 edit

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 [17] and allows the 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 edit

References edit

  1. ^ a b Dejanovic B, Semtner M, Ebert S, Lamkemeyer T, Neuser F, Lüscher B, Meier JC, Schwarz G (July 2014). "Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses". PLOS Biology. 12 (7): e1001908. doi:10.1371/journal.pbio.1001908. PMC 4099074. 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. ^ Rocks O, Peyker A, Kahms M, Verveer PJ, Koerner C, Lumbierres M, Kuhlmann J, Waldmann H, Wittinghofer A, Bastiaens PI (2005). "An acylation cycle regulates localization and activity of palmitoylated Ras isoforms". Science. 307 (5716): 1746–1752. Bibcode:2005Sci...307.1746R. doi:10.1126/science.1105654. PMID 15705808. 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. ^ Palese, Peter; García-Sastre, Adolfo (1999). "INFLUENZA VIRUSES (ORTHOMYXOVIRIDAE) | Molecular Biology". Encyclopedia of Virology. pp. 830–836. doi:10.1006/rwvi.1999.0157. ISBN 9780122270307. Archived from the original on 2012-09-12.
  6. ^ Wall, MA; Coleman, DE; Lee, E; Iñiguez-Lluhi, JA; Posner, BA; Gilman, AG; Sprang, SR (Dec 15, 1995). "The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2". Cell. 83 (6): 1047–58. doi:10.1016/0092-8674(95)90220-1. 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. ^ 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. PMC 5364179. 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. ^ 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. S2CID 56175691.
  11. ^ Sanders SS, Martin DD, Butland SL, Lavallée-Adam M, Calzolari D, Kay C, Yates JR, Hayden MR (August 2015). "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): e1004405. Bibcode:2015PLSCB..11E4405S. doi:10.1371/journal.pcbi.1004405. PMC 4537140. PMID 26275289.
  12. ^ 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. Bibcode:2010PNAS..10722050L. doi:10.1073/pnas.1016184107. PMC 3009825. PMID 21131568.
  13. ^ 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: 13873. Bibcode:2016NatCo...713873P. doi:10.1038/ncomms13873. PMC 5171650. PMID 27976674.
  14. ^ 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. PMC 6729126. PMID 31060927.
  15. ^ 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): 183091. doi:10.1016/j.bbamem.2019.183091. PMC 6907892. PMID 31672538.
  16. ^ 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. PMC 7306821.
  17. ^ Greaves, Jennifer (March 2011). "Differential palmitoylation regulates intracellular patterning of SNAP25". Journal of Cell Science. 124 (8): 1351–1360. doi:10.1242/jcs.079095. PMC 3065388. PMID 21429935.
  18. ^ "Molecular Mechanisms of Synaptogenesis." Edited by Alexander Dityatev and Alaa El-Husseini. Springer: New York, NY. 2006. pg. 72-75
  19. ^ Brigidi GS, Sun Y, Beccano-Kelly D, Pitman K, Jobasser M, Borgland SL, Milnerwood AJ, Bamji SX (January 23, 2014). "Palmitoylation of [delta]-catenin by DHHC5 mediates activity-induced synapse plasticity". Nature Neuroscience. 17 (4): 522–532. doi:10.1038/nn.3657. PMC 5025286. PMID 24562000.

Further reading edit

  • Smotrys J, Linder A (2004). "Palmitoylation of Intracellular Signaling Proteins: Regulation and Function". Annu Rev Biochem. 73: 559–87. doi:10.1146/annurev.biochem.73.011303.073954. PMID 15189153.
  • Resh, M. (2006) "Palmitoylation of Ligands, Receptors, and Intracellular Signaling Molecules". Sci STK. 359 October 31.
  • Linder M, Deschenes R (2007). "Palmitoylation: policing protein stability and traffic". Nature Reviews Molecular Cell Biology. 8 (1): 74–84. doi:10.1038/nrm2084. PMID 17183362. S2CID 26339042.

External links edit

  • CSS-Palm - Palmitoylation Site Prediction with a Clustering and Scoring Strategy
  • Swisspalm - S-Palmitoylation database

February 15, 2024
palmitoylation, confused, with, palmitoleoylation, covalent, attachment, fatty, acids, such, palmitic, acid, cysteine, palmitoylation, less, frequently, serine, threonine, palmitoylation, residues, proteins, which, typically, membrane, proteins, precise, funct. Not to be confused with Palmitoleoylation 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 2 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 3 as well as in modulating protein protein interactions 4 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 In palmitoylation a palmitoyl group derived from palmitic acid pictured above is added Palmitoylation of a cysteine residueLeft 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 An example of a protein that undergoes palmitoylation is hemagglutinin a membrane glycoprotein used by influenza to attach to host cell receptors 5 The palmitoylation cycles of a wide array of enzymes have been characterized in the past few years including H Ras Gsa the b2 adrenergic receptor and endothelial nitric oxide synthase eNOS In signal transduction via G protein palmitoylation of the a subunit prenylation of the g 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 Contents 1 Mechanism 2 The palmitoylome 3 Biological function 3 1 Substrate presentation 3 2 General Anesthesia 3 3 Synapse formation 4 See also 5 References 6 Further reading 7 External linksMechanism editS palmitoylation is generally done by proteins with the DHHC domain Exceptions exist in non enzymatic reactions Acyl protein thioesterase APT catalyses the reverse reaction 7 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 8 9 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 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 editA 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 11 Biological function editSubstrate presentation edit 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 edit 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 edit 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 17 and allows the 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 editDHHC domain Myristoylation Myelin proteolipid protein Palmitoleoylation Prenylation Membrane mediated anesthesiaReferences edit a b Dejanovic B Semtner M Ebert S Lamkemeyer T Neuser F Luscher B Meier JC Schwarz G July 2014 Palmitoylation of gephyrin controls receptor clustering and plasticity of GABAergic synapses PLOS Biology 12 7 e1001908 doi 10 1371 journal pbio 1001908 PMC 4099074 PMID 25025157 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 Rocks O Peyker A Kahms M Verveer PJ Koerner C Lumbierres M Kuhlmann J Waldmann H Wittinghofer A Bastiaens PI 2005 An acylation cycle regulates localization and activity of palmitoylated Ras isoforms Science 307 5716 1746 1752 Bibcode 2005Sci 307 1746R doi 10 1126 science 1105654 PMID 15705808 S2CID 12408991 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 Palese Peter Garcia Sastre Adolfo 1999 INFLUENZA VIRUSES ORTHOMYXOVIRIDAE Molecular Biology Encyclopedia of Virology pp 830 836 doi 10 1006 rwvi 1999 0157 ISBN 9780122270307 Archived from the original on 2012 09 12 Wall MA Coleman DE Lee E Iniguez Lluhi JA Posner BA Gilman AG Sprang SR Dec 15 1995 The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2 Cell 83 6 1047 58 doi 10 1016 0092 8674 95 90220 1 PMID 8521505 a b Lanyon Hogg T Faronato M Serwa R A amp 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 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 PMC 5364179 PMID 28392791 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 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 S2CID 56175691 Sanders SS Martin DD Butland SL Lavallee Adam M Calzolari D Kay C Yates JR Hayden MR August 2015 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 e1004405 Bibcode 2015PLSCB 11E4405S doi 10 1371 journal pcbi 1004405 PMC 4537140 PMID 26275289 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 Bibcode 2010PNAS 10722050L doi 10 1073 pnas 1016184107 PMC 3009825 PMID 21131568 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 13873 Bibcode 2016NatCo 713873P doi 10 1038 ncomms13873 PMC 5171650 PMID 27976674 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 PMC 6729126 PMID 31060927 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 183091 doi 10 1016 j bbamem 2019 183091 PMC 6907892 PMID 31672538 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 PMC 7306821 Greaves Jennifer March 2011 Differential palmitoylation regulates intracellular patterning of SNAP25 Journal of Cell Science 124 8 1351 1360 doi 10 1242 jcs 079095 PMC 3065388 PMID 21429935 Molecular Mechanisms of Synaptogenesis Edited by Alexander Dityatev and Alaa El Husseini Springer New York NY 2006 pg 72 75 Brigidi GS Sun Y Beccano Kelly D Pitman K Jobasser M Borgland SL Milnerwood AJ Bamji SX January 23 2014 Palmitoylation of delta catenin by DHHC5 mediates activity induced synapse plasticity Nature Neuroscience 17 4 522 532 doi 10 1038 nn 3657 PMC 5025286 PMID 24562000 Further reading editSmotrys J Linder A 2004 Palmitoylation of Intracellular Signaling Proteins Regulation and Function Annu Rev Biochem 73 559 87 doi 10 1146 annurev biochem 73 011303 073954 PMID 15189153 Resh M 2006 Palmitoylation of Ligands Receptors and Intracellular Signaling Molecules Sci STK 359 October 31 Linder M Deschenes R 2007 Palmitoylation policing protein stability and traffic Nature Reviews Molecular Cell Biology 8 1 74 84 doi 10 1038 nrm2084 PMID 17183362 S2CID 26339042 External links editCSS Palm Palmitoylation Site Prediction with a Clustering and Scoring Strategy CKSAAP Palm Swisspalm S Palmitoylation database Retrieved from https en wikipedia org w index php title Palmitoylation amp oldid 1205576944, wikipedia, wiki, book, books, library,

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