Dataset Information

Protein depalmitoylases.

ABSTRACT: Protein depalmitoylation describes the removal of thioester-linked long chain fatty acids from cysteine residues in proteins. For many S-palmitoylated proteins, this process is promoted by acyl protein thioesterase enzymes, which catalyze thioester hydrolysis to solubilize and displace substrate proteins from membranes. The closely related enzymes acyl protein thioesterase 1 (APT1; LYPLA1) and acyl protein thioesterase 2 (APT2; LYPLA2) were initially identified from biochemical assays as G protein depalmitoylases, yet later were shown to accept a number of S-palmitoylated protein and phospholipid substrates. Leveraging the development of isoform-selective APT inhibitors, several studies report distinct roles for APT enzymes in growth factor and hormonal signaling. Recent crystal structures of APT1 and APT2 reveal convergent acyl binding channels, suggesting additional factors beyond acyl chain recognition mediate substrate selection. In addition to APT enzymes, the ABHD17 family of hydrolases contributes to the depalmitoylation of Ras-family GTPases and synaptic proteins. Overall, enzymatic depalmitoylation ensures efficient membrane targeting by balancing the palmitoylation cycle, and may play additional roles in signaling, growth, and cell organization. In this review, we provide a perspective on the biochemical, structural, and cellular analysis of protein depalmitoylases, and outline opportunities for future studies of systems-wide analysis of protein depalmitoylation.

SUBMITTER: Won SJ

PROVIDER: S-EPMC6009847 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Protein depalmitoylases.

Won Sang Joon SJ Cheung See Kit Melanie M Martin Brent R BR

Critical reviews in biochemistry and molecular biology 20171214 1

Protein depalmitoylation describes the removal of thioester-linked long chain fatty acids from cysteine residues in proteins. For many S-palmitoylated proteins, this process is promoted by acyl protein thioesterase enzymes, which catalyze thioester hydrolysis to solubilize and displace substrate proteins from membranes. The closely related enzymes acyl protein thioesterase 1 (APT1; LYPLA1) and acyl protein thioesterase 2 (APT2; LYPLA2) were initially identified from biochemical assays as G prote ...[more]

PMID: 29239216

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Project description:While lipids were first appreciated as a critical hydrophobic barrier, our understanding of their roles at the cellular and organismal levels continues to grow. Not only are they important independent operators, providing a platform for both static and dynamic organization and communication within the cell, they also exert significant effects via the chemical modification of proteins. Addition of a lipid post-translational modification (PTM) alters protein hydrophobicity and behavior, with distinct consequences for subcellular trafficking, localization, intra- and intermolecular interactions, and stability. One of the most abundant and widespread protein lipidation events is S-acylation, installation of a long-chain lipid to the thiol of a cysteine side chain through a thioester linkage. S-Acylation is often referred to as S-palmitoylation, due to the prevalence of palmitate as the lipid modification. Unlike many lipid PTMs, S-acylation is enzymatically reversible, enabling the cell to tune proteome-wide properties through dynamic alterations in protein lipidation status. While much has been uncovered about the molecular effects of S-acylation and its implications for physiology, current biochemical and chemical methods only assess substrate lipidation levels or steady-state levels of enzyme activity. Yet, the writer protein acyl transferases (PATs) and eraser acyl protein thioesterases (APTs) are dynamically active, responsible for sometimes-rapid changes in S-palmitoylation status of target proteins. Thus, to understand the full scope, significance, and subtlety of S-deacylation and its regulation in the cell, it is necessary to observe the timing and cellular geography of regulatory enzyme activities. In this Account, we review the chemical tools developed by our group to selectively visualize and perturb the activity of APTs in live cells, highlighting the biological insights gained from their application. To visualize APT activity, we masked fluorogenic molecules with thioacylated, peptide-based APT substrate mimetics; APT activity and thus thiol deprotection releases a fluorescent product in the turn-on depalmitoylation probes (DPPs), while in ratiometric depalmitoylation probes (RDPs) the emission of the parent fluorophore is altered. Application of these probes in live cells reveals that APT activity is sensitive to cell signaling events and metabolic disturbances. Additionally, as indicated above, the location of regulatory enzymes is critical in lipid signaling, and one organelle of particular interest, due to its role in maintaining cellular homeostasis and its legion of lipidated proteins, is the mitochondria. Therefore, we developed a class of spatially constrained mitoDPPs to visualize mitochondrial APT activity as well as a selective inhibitor of mitochondrial deacylation activity, mitoFP. With these tools, we identify two mitochondrial S-depalmitoylases and connect mitochondrial S-depalmitoylation to redox buffering capacity. Moreover, some of the changes in activity observed are specific to the mitochondria, confirming spatial as well as temporal regulation of eraser protein activity. Overall, this chemical toolkit for S-depalmitoylase activity, imaging reagents and a targeted inhibitor, will continue to illuminate the regulatory mechanisms and roles of S-depalmitoylation within the complex homeostatic networks of the cell.

Dataset Information

Protein depalmitoylases.

Publications

Protein depalmitoylases.

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