Posttranslational modifications (PTMs) refer to amino acid side chain modification in some proteins after their biosynthesis. There are more than 400 different types of PTMs affecting many aspects of protein functions. Such modifications happen as crucial molecular regulatory mechanisms to regulate diverse cellular processes. These processes have a significant impact on the structure and function of proteins. Disruption in PTMs can lead to the dysfunction of vital biological processes and hence to various diseases. High-throughput experimental methods for discovery of PTMs are very laborious and time-consuming. Therefore, there is an urgent need for computational methods and powerful tools to predict PTMs. There are vast amounts of PTMs data, which are publicly accessible through many online databases. In this survey, we comprehensively reviewed the major online databases and related tools. The current challenges of computational methods were reviewed in detail as well.

/pdf/post-translational-modifications-in-proteins-resources-tools-2ua57pvx6f.pdf

Post-translational modifications in proteins: resources, tools and prediction methods

Protein Lipidation in Cell Signaling and Diseases: Function, Regulation, and Therapeutic Opportunities.

S-Acylation (commonly referred to as S-palmitoylation) is a post-translational modification consisting in the covalent attachment of an acyl chain to a cysteine residue of the target protein. The lability of the resulting thioester bond gives S-acylation an essential characteristic: its reversibility. S-acylation dynamically regulates different aspects in the life of a protein (including stability, localization, interactome, and function) and, thus, plays critical roles in cellular physiology. For long, the reversibility of S-acylation has been neglected and thereby its potential as a regulatory mechanism for protein function undervalued. Thanks to technological advances, the field has now entered its golden era. A great diversity of interesting targets is being identified, the physio-pathological importance of the modification is starting to be revealed, structural information on the enzymes is becoming available, and the regulatory dynamics are gradually being understood. Here we will review the most recent literature in the S-acylation field, with a special focus on the molecular aspects of the modification, its regulation, and its consequences.

The molecular era of protein S-acylation: spotlight on structure, mechanisms, and dynamics.

AIMS
Impaired fatty acid oxidation (FAO) in mitochondria of hepatocytes causes lipid accumulation and excessive production of ROS and oxidative damage, as a result leads to nonalcoholic fatty liver disease (NAFLD). Fatty acid translocase (FAT/CD36), a transmembrane protein that facilitates the uptake of long-chain fatty acids (LCFAs), is recently found to be involved in FAO. The function of FAT/CD36 is associated with its subcellular localization. Palmitoylation, one of the most common lipid modifications, is generally thought to regulate FAT/CD36 subcellular localization. Here, we aimed to investigate the role of palmitoylation in FAT/CD36 localization to mitochondria and its influence on FAO in hepatocytes.


RESULTS
We demonstrated that FAT/CD36 exists on the mitochondria of hepatocytes. Palmitoylation of FAT/CD36 was significantly up-regulated in NAFLD. Inhibition of FAT/CD36 palmitoylation resulted in an obvious increase in the distribution of FAT/CD36 to mitochondria of hepatocytes. Depalmitoylated FAT/CD36 on the mitochondrial membrane continues functioning by facilitating fatty acid trafficking to mitochondria. Abundant mitochondrial FAT/CD36 interacted with long-chain acyl-CoA synthetase 1 (ACSL1), and thus, more LCFAs were transported to ACSL1. This led to an increase in the generation of long-chain acyl-CoA, contributing to the enhancement of FAO and alleviating NAFLD. Innovation and Conclusion: This work revealed that inhibiting FAT/CD36 palmitoylation alleviates NAFLD by promoting FAT/CD36 localization to the mitochondria of hepatocytes. Mitochondrial FAT/CD36 functions as a molecular bridge between LCFAs and ACSL1 to increase the production of long-chain acyl-CoA thus promoting FAO, thereby avoiding lipid accumulation and over-production of ROS in hepatocytes.

Inhibition of fatty acid translocase (FAT/CD36) palmitoylation enhances hepatic fatty acid β-oxidation by increasing its localization to mitochondria and interaction with long-chain acyl-CoA synthetase 1.

Morphogenesis of many protozoans depends on a polarized establishment of cytoskeletal structures. In malaria-causing parasites, this can be observed when a round zygote develops into an elongated motile ookinete within the mosquito stomach. This morphogenesis is mediated by the pellicle cytoskeletal structures, including the inner membrane complex (IMC) and the underlying subpellicular microtubules (SPMs). How the parasite maintains the IMC-SPM connection and establishes a dome-like structure of SPM to support cell elongation is unclear. Here, we show that palmitoylation of N-terminal cysteines of two IMC proteins (ISP1/ISP3) regulates the IMC localization of ISP1/ISP3 and zygote-to-ookinete differentiation. Palmitoylation of ISP1/ISP3 is catalyzed by an IMC-residing palmitoyl-S-acyl-transferase (PAT) DHHC2. Surprisingly, DHHC2 undergoes self-palmitoylation at C-terminal cysteines via its PAT activity, which controls DHHC2 localization in IMC after zygote formation. IMC-anchored ISP1 and ISP3 interact with microtubule component β-tubulin, serving as tethers to maintain the proper structure of SPM during zygote elongation. This study identifies the first PAT-substrate pair in malaria parasites and uncovers a protein palmitoylation cascade regulating microtubule cytoskeleton.

https://www.embopress.org/doi/epdf/10.15252/embj.2019104168

A protein palmitoylation cascade regulates microtubule cytoskeleton integrity in Plasmodium.

Dynamic post-translational modifications allow the rapid, specific, and tunable regulation of protein functions in eukaryotic cells. S-acylation is the only reversible lipid modification of proteins, in which a fatty acid, usually palmitate, is covalently attached to a cysteine residue of a protein by a zDHHC palmitoyl acyltransferase enzyme. Depalmitoylation is required for acylation homeostasis and is catalyzed by an enzyme from the alpha/beta hydrolase family of proteins usually acyl-protein thioesterase (APT1). The enzyme responsible for depalmitoylation in Trypanosoma brucei parasites is currently unknown. We demonstrate depalmitoylation activity in live bloodstream and procyclic form trypanosomes sensitive to dose-dependent inhibition with the depalmitoylation inhibitor, palmostatin B. We identified a homologue of human APT1 in Trypanosoma brucei which we named TbAPT-like (TbAPT-L). Epitope-tagging of TbAPT-L at N- and C- termini indicated a cytoplasmic localization. Knockdown or over-expression of TbAPT-L in bloodstream forms led to robust changes in TbAPT-L mRNA and protein expression but had no effect on parasite growth in vitro, or cellular depalmitoylation activity. Esterase activity in cell lysates was also unchanged when TbAPT-L was modulated. Unexpectedly, recombinant TbAPT-L possesses esterase activity with specificity for short- and medium-chain fatty acid substrates, leading to the conclusion, TbAPT-L is a lipase, not a depalmitoylase.

/pdf/trypanosoma-brucei-acyl-protein-thioesterase-like-tbapt-l-is-3dbf6eug.pdf

Trypanosoma brucei Acyl-Protein Thioesterase-like (TbAPT-L) Is a Lipase with Esterase Activity for Short and Medium-Chain Fatty Acids but Has No Depalmitoylation Activity

Eukaryotic parasites possess complex life cycles and utilize an assortment of molecular mechanisms to overcome physical barriers, suppress and/or bypass the host immune response, including invading host cells where they can replicate in a protected intracellular niche. Protein S-palmitoylation is a dynamic post-translational modification in which the fatty acid palmitate is covalently linked to cysteine residues on proteins by the enzyme palmitoyl acyltransferase (PAT) and can be removed by lysosomal palmitoyl-protein thioesterase (PPT) or cytosolic acyl-protein thioesterase (APT). In addition to anchoring proteins to intracellular membranes, functions of dynamic palmitoylation include - targeting proteins to specific intracellular compartments via trafficking pathways, regulating the cycling of proteins between membranes, modulating protein function and regulating protein stability. Recent studies in the eukaryotic parasites - Plasmodium falciparum, Toxoplasma gondii, Trypanosoma brucei, Cryptococcus neoformans and Giardia lamblia - have identified large families of PATs and palmitoylated proteins. Many palmitoylated proteins are important for diverse aspects of pathogenesis, including differentiation into infective life cycle stages, biogenesis and tethering of secretory organelles, assembling the machinery powering motility and targeting virulence factors to the plasma membrane. This review aims to summarize our current knowledge of palmitoylation in eukaryotic parasites, highlighting five exemplary mechanisms of parasite virulence dependent on palmitoylation.

Dynamic protein S-palmitoylation mediates parasite life cycle progression and diverse mechanisms of virulence

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Trypanosoma brucei Acyl-Protein Thioesterase-like (TbAPT-L) Is a Lipase with Esterase Activity for Short and Medium-Chain Fatty Acids but Has No Depalmitoylation Activity

Dynamic protein S-palmitoylation mediates parasite life cycle progression and diverse mechanisms of virulence