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

Abstract

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.

Low-background Acyl-biotinyl Exchange Largely Eliminates the Co-isolation of Non-S-acylated Proteins and Enables Deep S-acylproteomic Analysis

“…So far, many global S-acylproteomic studies were performed using ABE and its derived methods, which are independent of metabolic labeling and have the potential of capturing the entire S-acylproteome in any biological samples including tissues and extracellular vesicles in biofluids. 5,26 In theory, ABE methods are able to capture more S-acylated proteins than other methods such as MLCC, which is biased towards the enrichment of S-acylated proteins with rapid turnover. 5 Nevertheless, an analysis of S-acylated proteins compiled in the SwissPalm (v2) 3 -a comprehensive database of Sacylated proteins identified since 1981-revealed that only 41% (1,173 out of 2,881) of the human S-acylproteome and 33% (976 out of 2,939) of the mouse S-acylproteome were discovered by ABE studies ( Fig.…”

Comprehensive palmitoyl-proteomic analysis identifies distinct protein signatures for large and small cancer-derived extracellular vesicles

“…Functional enrichment analysis identified a series of cell functions overrepresented in EVs in comparison to M. More specifically, the palmitoylproteins significantly enriched in both L-and S-EVs were involved in pyridine nucleotide metabolism and cell adhesion ( Figure 3B and Suppl. Table 2), including proteins known to be involved in modulating cell polarity, adhesion and migration 46 . These comprised membrane-anchored integrins (ITGA2, ITGA6, ATGB4), claudins (CLDN1, CLDN1), and cytoskeletal proteins such as the Rho-associated moesin (MSN), vinculin (VCL), ezrin (EZR), ROCK2 and the Ras GTPase-activating-like protein IQGAP1 (Suppl.…”

Hemagglutinin of Influenza A, but not of Influenza B and C viruses is acylated by ZDHHC2, 8, 15 and 20

“…Enzymes that acylate HA (or any other viral glycoprotein) have not been identified, but cellular proteins are acylated by members of the ZDHHC family of proteins [27][28][29][30]. ZDHHC proteins are polytopic membrane proteins containing an Asp-His-His-Cys (DHHC) motif as the catalytic centre in one of their cytoplasmic domains.…”