Palmitoylation

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Palmitoylation is a post-translational modification PTM based on thioester-linkage between palmitic acid and the cysteine residue of a protein. This covalent attachment of palmitate is reversibly and dynamically regulated by two opposing sets of enzymes: palmitoyl acyltransferases containing a zinc finger aspartate-histidine-histidine-cysteine motif PAT-DHHCs and thioesterases. The reversible nature of palmitoylation enables fine-tuned regulation of protein conformation, stability, and ability to interact with other proteins. More importantly, the proper function of many surface receptors and signaling proteins requires palmitoylation-meditated partitioning into lipid rafts. This review provides the latest findings of palmitoylated proteins in leukocytes and focuses on the functional impact of palmitoylation in leukocyte function related to adhesion, transmigration, chemotaxis, phagocytosis, pathogen recognition, signaling activation, cytotoxicity, and cytokine production.

Palmitoylation

Federal government websites often end in. The site is secure. Proteins encoded by several oncogenes and tumor suppressors are modified by palmitoylation, which enhances the hydrophobicity of specific protein subdomains, and can confer changes in protein stability, membrane localization, protein—protein interaction, and signal transduction. The importance for protein palmitoylation in tumorigenesis has just started to be elucidated in the past decade; palmitoylation appears to affect key aspects of cancer, including cancer cell proliferation and survival, cell invasion and metastasis, and antitumor immunity. Here we review the current literature on protein palmitoylation in the various cancer types, and discuss the potential of targeting of palmitoylation enzymes or palmitoylated proteins for tumor treatment. Several oncogenes and tumor suppressors are modified by protein palmitoylation, a process that is dynamically controlled by the ZDHHC and PPT enzyme families, which add and remove palmitate, respectively. Palmitoylation affects protein stability, protein—protein interactions, membrane localization, and signaling transduction, thereby regulating tumor survival and tumor progression. Palmitoylation enzymes or palmitoylated proteins are potential targets for tumor treatment. Tumorigenesis is characterized by persistent cell proliferation, resistance to cell death, sustained angiogenesis, and increased cell invasion and metastasis. These features are accompanied by genome instability and mutation, cellular metabolism, replicative immortality, sustained inflammation, evasion of growth suppressors, and immune suppression [ 1 ]. The above processes are often controlled by various oncogenes and tumor suppressors, many of which are modified by posttranslational modifications PTMs , such as phosphorylation, acetylation, ubiquitination, and palmitoylation [ 2 , 3 ]. Palmitate is converted from fatty acids by fatty acid synthase FASN [ 5 ]. Schematic diagram of fatty acid metabolism to generate palmitic acid. The mechanisms of the palmitoylated proteins in human cancers.

These examples strengthen the notion that palmitoylation regulates tumorigenesis in both directions, palmitoylation.

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. 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. 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. S-palmitoylation is generally done by proteins with the DHHC domain.

Federal government websites often end in. The site is secure. Preview improvements coming to the PMC website in October Learn More or Try it out now. A plethora of novel information has emerged over the past decade regarding protein lipidation. The reversible attachment of palmitic acid to cysteine residues, termed S -palmitoylation, has focused a special attention. This is mainly due to the unique role of this modification in the regulation of protein trafficking and function.

Palmitoylation

Federal government websites often end in. The site is secure. Preview improvements coming to the PMC website in October Learn More or Try it out now. Protein palmitoylation is a widespread lipid modification in which one or more cysteine thiols on a substrate protein are modified to form a thioester with a palmitoyl group. This lipid modification is readily reversible; a feature of protein palmitoylation that allows for rapid regulation of the function of many cellular proteins. Mutations in palmitoyltransferases PATs , the enzymes that catalyze the formation of this modification, are associated with a number of neurological diseases and cancer progression. This review summarizes the crucial role of palmitoylation in biological systems, the discovery of the DHHC protein family that catalyzes protein palmitoylation, and the development of methods for investigating the catalytic mechanism of PATs. In addition, a protein can be modified with a lipid anchor under enzymatic control that interacts with the lipid bilayer and localizes proteins to the membrane surface. Lipid modifications are increasingly recognized as important mechanisms for both targeting proteins to the membrane and subcellular protein trafficking.

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Shows a role for palmitoylation as a mechanism to protect a protein from degradation by inhibiting trafficking to a compartment where the protein is ubiquitylated. People also looked at. World J Gastroenterol. Therefore, this method is useful for the initial identification of PATs but is not generally suitable for further mechanistic characterization of the enzymes. Palmitoylation was shown to be closely related to the progression of colorectal cancer CRC [ 45 , 46 ]. A fluorescence-based high performance liquid chromatographic method for the characterization of palmitoyl acyl transferase activity. Cell 16 , — Thorens B, Mueckler M. Zingler, P. Ethics declarations Competing interests The authors declare no competing financial interests. Although both trans- and auto-palmitoylation disappear when mutations are made in the DHHC domain of PATs, there is not yet any direct evidence that the DHHC cysteine is the site of auto-palmitoylation. Several palmitoylation assays have been developed and used to study PATs; each assay has both advantages and disadvantages LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation. FEBS Lett.

S -palmitoylation is a reversible, enzymatic posttranslational modification of proteins in which palmitoyl chain is attached to a cysteine residue via a thioester linkage.

Basu J. In this case, the palmitoylated proteins are subjected to protease digestion and the resulting peptides are separated by chromatography. Lancaster, G. STING palmitoylation as a therapeutic target. Acta , — In individuals with the disease, the polyglutamine sequence is expanded to more than 40 residues. Impaired activation and localization of LAT in anergic T cells as a consequence of a selective palmitoylation defect. Kong, E. An organelle of the late endosomal pathway that contains internal vesicles formed by the invagination of the limiting membrane of the endosome. Curation of the mammalian palmitoylome indicates a pivotal role for palmitoylation in diseases and disorders of the nervous system and cancers. Methods 6, — Localization of the palmitoylation site in the transmembrane protein p12E of Friend murine leukemia virus. DHHCs are transmembrane proteins that span the membrane four to six times and locate on the cytosolic face of the membrane Blaskovic et al. Cell Adh Migr. Ochsenbauer-Jambor, C.