Abstract
Protein S-acylation is the reversible addition of fatty acids to the cysteine residues of target proteins. It regulates multiple aspects of protein function, including the localization to membranes, intracellular trafficking, protein interactions, protein stability, and protein conformation. This process is regulated by palmitoyl acyltransferases that have the conserved amino acid sequence DHHC at their active site. Although they have conserved catalytic cores, DHHC enzymes vary in their protein substrate selection, lipid substrate preference, and regulatory mechanisms. Alterations in DHHC enzyme function are associated with many human diseases, including cancers and neurological conditions. The removal of fatty acids from acylated cysteine residues is catalyzed by acyl protein thioesterases. Notably, S-acylation is now known to be a highly dynamic process, and plays crucial roles in signaling transduction in various cell types. In this review, we will explore the recent findings on protein S-acylation, the enzymatic regulation of this process, and discuss examples of dynamic S-acylation.
Highlights
Protein lipidation is the co-translational or post-translational covalent addition of a variety of lipids to target proteins
It is worth noting that in our study, we found that the acylation of the DHHC5 C-terminal tail did not affect its autoacylation at the catalytic core
We recently showed an alternative mechanism for Gα acylation that requires stimulusdependent plasma membrane DHHC5 activation (Chen et al, 2020)
Summary
Protein lipidation is the co-translational or post-translational covalent addition of a variety of lipids to target proteins. The possible protective mechanism by which S-acylation prevents TBC1D3 binding to CUL7 is by sequestering the protein to lipid rafts or by altering its conformation Another example of S-acylation regulating protein stability on the plasma membrane is the Fas death receptor (FasR). By using fluorescence resonance energy transfer (FRET) in live cells, it was recently found that the dynamic palmitoylation of sodium-calcium exchanger 1 (NCX1) leads to rearrangement of the f-loop region and regulate its dimerization (Gök et al, 2020) These acylation-induced changes are key in recruiting the exchange inhibitory peptide and mediating Ca2+ influx. It has been shown that S-acylation-induced conformational changes are important for its activation and the excitability of cardiac cells
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