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Journal of Molecular Biology Aug 2020S-acylation, whereby a fatty acid chain is covalently linked to a cysteine residue by a thioester linkage, is the most prevalent kind of lipid modification of proteins.... (Review)
Review
S-acylation, whereby a fatty acid chain is covalently linked to a cysteine residue by a thioester linkage, is the most prevalent kind of lipid modification of proteins. Thousands of proteins are targets of this post-translational modification, which is catalyzed by a family of eukaryotic integral membrane enzymes known as DHHC protein acyltransferases (DHHC-PATs). Our knowledge of the repertoire of S-acylated proteins has been rapidly expanding owing to development of the chemoproteomic techniques. There has also been an increasing number of reports in the literature documenting the importance of S-acylation in human physiology and disease. Recently, the first atomic structures of two different DHHC-PATs were determined using X-ray crystallography. This review will focus on the insights gained into the molecular mechanism of DHHC-PATs from these structures and highlight representative data from the biochemical literature that they help explain.
Topics: Acylation; Acyltransferases; Crystallography, X-Ray; Humans; Models, Molecular; Protein Domains; Protein Processing, Post-Translational
PubMed: 32522557
DOI: 10.1016/j.jmb.2020.05.023 -
Science Translational Medicine May 2022Posttranslational modifications contribute to the pathology of methylmalonic acidemia and may be targetable via an acylation-resistant sirtuin (Head , this issue). (Review)
Review
Posttranslational modifications contribute to the pathology of methylmalonic acidemia and may be targetable via an acylation-resistant sirtuin (Head , this issue).
Topics: Acylation; Amino Acid Metabolism, Inborn Errors; Humans; Lysine; Protein Processing, Post-Translational
PubMed: 35613282
DOI: 10.1126/scitranslmed.abq4863 -
Genomics, Proteomics & Bioinformatics Dec 2016
Topics: Acylation; Histones; Humans; Reading
PubMed: 28007607
DOI: 10.1016/j.gpb.2016.12.001 -
Organic & Biomolecular Chemistry Jan 2021DNAzymes were previously identified by in vitro selection for a variety of chemical reactions, including several biologically relevant peptide modifications. However,...
DNAzymes were previously identified by in vitro selection for a variety of chemical reactions, including several biologically relevant peptide modifications. However, finding DNAzymes for peptide lysine acylation is a substantial challenge. By using suitably reactive aryl ester acyl donors as the electrophiles, here we used in vitro selection to identify DNAzymes that acylate amines, including lysine side chains of DNA-anchored peptides. Some of the DNAzymes can transfer a small glutaryl group to an amino group. These results expand the scope of DNAzyme catalysis and suggest the future broader applicability of DNAzymes for sequence-selective lysine acylation of peptide and protein substrates.
Topics: Acylation; Amines; Biocatalysis; DNA, Catalytic; Lysine; Peptides
PubMed: 33150349
DOI: 10.1039/d0ob02015j -
Molecules (Basel, Switzerland) Jul 2021The nature-identical engineered polysaccharide α-(1,3) glucan, produced by the enzymatic polymerization of sucrose, was chemically modified by acylation with succinic...
The nature-identical engineered polysaccharide α-(1,3) glucan, produced by the enzymatic polymerization of sucrose, was chemically modified by acylation with succinic anhydride. This modification reaction was initially performed at the micro scale in a TGA reactor to access a range of reaction conditions and to study the mechanism of the reaction. Subsequently, the best performing conditions were reproduced at the larger laboratory scale. The reaction products were characterized via coupled TGA/DSC analysis, FT-IR spectroscopy, solution viscosity and pH determination. The acylation path resulted in partially modifying the polysaccharide by altering its behavior in terms of thermal properties and solubility. The acylation in a solvent-free approach was found promising for the development of novel, potentially melt-processable and fully bio-based and biodegradable ester compounds.
Topics: Acylation; Glucans; Hydrogen-Ion Concentration; Polymerization; Succinic Anhydrides; Sucrose; Viscosity
PubMed: 34279397
DOI: 10.3390/molecules26134058 -
The EMBO Journal Jul 2023Brassinosteroids (BRs) are important plant hormones involved in many aspects of development. Here, we show that BRASSINOSTEROID SIGNALING KINASEs (BSKs), key components...
Brassinosteroids (BRs) are important plant hormones involved in many aspects of development. Here, we show that BRASSINOSTEROID SIGNALING KINASEs (BSKs), key components of the BR pathway, are precisely controlled via de-S-acylation mediated by the defense hormone salicylic acid (SA). Most Arabidopsis BSK members are substrates of S-acylation, a reversible protein lipidation that is essential for their membrane localization and physiological function. We establish that SA interferes with the plasma membrane localization and function of BSKs by decreasing their S-acylation levels, identifying ABAPT11 (ALPHA/BETA HYDROLASE DOMAIN-CONTAINING PROTEIN 17-LIKE ACYL PROTEIN THIOESTERASE 11) as an enzyme whose expression is quickly induced by SA. ABAPT11 de-S-acylates most BSK family members, thus integrating BR and SA signaling for the control of plant development. In summary, we show that BSK-mediated BR signaling is regulated by SA-induced protein de-S-acylation, which improves our understanding of the function of protein modifications in plant hormone cross talk.
Topics: Brassinosteroids; Arabidopsis Proteins; Salicylic Acid; Arabidopsis; Plant Growth Regulators; Acylation; Gene Expression Regulation, Plant
PubMed: 37211868
DOI: 10.15252/embj.2022112998 -
The Journal of Cell Biology Nov 2023With a limited number of genes, cells achieve remarkable diversity. This is to a large extent achieved by chemical posttranslational modifications of proteins. Amongst...
With a limited number of genes, cells achieve remarkable diversity. This is to a large extent achieved by chemical posttranslational modifications of proteins. Amongst these are the lipid modifications that have the unique ability to confer hydrophobicity. The last decade has revealed that lipid modifications of proteins are extremely frequent and affect a great variety of cellular pathways and physiological processes. This is particularly true for S-acylation, the only reversible lipid modification. The enzymes involved in S-acylation and deacylation are only starting to be understood, and the list of proteins that undergo this modification is ever-increasing. We will describe the state of knowledge on the enzymes that regulate S-acylation, from their structure to their regulation, how S-acylation influences target proteins, and finally will offer a perspective on how alterations in the balance between S-acylation and deacylation may contribute to disease.
Topics: Acylation; Lipid Metabolism; Protein Processing, Post-Translational; Lipids
PubMed: 37756661
DOI: 10.1083/jcb.202307103 -
Current Opinion in Chemical Biology Dec 2021Protein S-fatty acylation or S-palmitoylation is a reversible and regulated lipid post-translational modification (PTM) in eukaryotes. Loss-of-function mutagenesis... (Review)
Review
Protein S-fatty acylation or S-palmitoylation is a reversible and regulated lipid post-translational modification (PTM) in eukaryotes. Loss-of-function mutagenesis studies have suggested important roles for protein S-fatty acylation in many fundamental biological pathways in development, neurobiology, and immunity that are also associated with human diseases. However, the hydrophobicity and reversibility of this PTM have made site-specific gain-of-function studies more challenging to investigate. In this review, we summarize recent chemical biology approaches and methods that have enabled site-specific gain-of-function studies of protein S-fatty acylation and the investigation of the mechanisms and significance of this PTM in eukaryotic biology.
Topics: Acylation; Humans; Lipoylation; Protein Processing, Post-Translational; Protein S
PubMed: 34333222
DOI: 10.1016/j.cbpa.2021.06.004 -
Nature Communications Jan 2023The complex architecture of the endoplasmic reticulum (ER) comprises distinct dynamic features, many at the nanoscale, that enable the coexistence of the nuclear...
The complex architecture of the endoplasmic reticulum (ER) comprises distinct dynamic features, many at the nanoscale, that enable the coexistence of the nuclear envelope, regions of dense sheets and a branched tubular network that spans the cytoplasm. A key player in the formation of ER sheets is cytoskeleton-linking membrane protein 63 (CLIMP-63). The mechanisms by which CLIMP-63 coordinates ER structure remain elusive. Here, we address the impact of S-acylation, a reversible post-translational lipid modification, on CLIMP-63 cellular distribution and function. Combining native mass-spectrometry, with kinetic analysis of acylation and deacylation, and data-driven mathematical modelling, we obtain in-depth understanding of the CLIMP-63 life cycle. In the ER, it assembles into trimeric units. These occasionally exit the ER to reach the plasma membrane. However, the majority undergoes S-acylation by ZDHHC6 in the ER where they further assemble into highly stable super-complexes. Using super-resolution microscopy and focused ion beam electron microscopy, we show that CLIMP-63 acylation-deacylation controls the abundance and fenestration of ER sheets. Overall, this study uncovers a dynamic lipid post-translational regulation of ER architecture.
Topics: Membrane Proteins; Kinetics; Endoplasmic Reticulum; Acylation; Lipids
PubMed: 36650170
DOI: 10.1038/s41467-023-35921-6 -
Talanta Jan 2023for the analysis of cannabinoids in bio-matrices are continually improved to achieve best possible sensitivity in their detection and accurate quantification. It has...
for the analysis of cannabinoids in bio-matrices are continually improved to achieve best possible sensitivity in their detection and accurate quantification. It has been well documented that CBD cyclizes to Δ9-THC and Δ9-THC isomerizes to Δ8-THC under acidic conditions by means of a Lewis-acid-catalyzed process, causing difficulty in accurate quantification of Δ9-THC in the presence of CBD, of CBD itself and of Δ9-THC itself when these compounds have to be derivatized by acylation. The present paper shows that CBD cyclization and Δ9-THC isomerization can be blocked by tertiary amines or azines, which capture protons appearing in the derivatizing mixture during acylation. The efficiency of the described acylation of CBD depends on the time and temperature of the derivatizing process, whereas the degree of CBD acylation, i.e. the synthesis of mono- or di-acylate CBD derivative, depends on the mutual ratio of the cannabinoid, the acylating agent and the proton binding compound. The way of mono- and di-acyl CBD derivatives formation described in the paper has not been reported yet. The paper contains a comprehensive analytical characterization of two types of CBD acyl derivatives, CBD-TFA and CBD-Ac, obtained by NMR, GC-MS and LC-MS.
Topics: Acylation; Amines; Cannabidiol; Cannabinoids; Dronabinol; Protons
PubMed: 36075144
DOI: 10.1016/j.talanta.2022.123777