Differential S-Acylation of Viral and Cellular Proteins: Structural Determinants, Enzymes, and Putative Functional...

S-acylation is post-translational attachment of fatty acid residues, mostly palmitoyl-groups to cysteines. This lipid modification could influence protein oligomerization, localization, and topology within the membrane, and could play a regulatory role in cellular signaling. Improvements in the experimental techniques, specifically, MALDI-TOF MS, have elevated the study of S-acylation to a level of refined detail. It was possible to conclusively show that, beyond palmitate, other types of fatty acids, such as stearate and oleate could be attached to the specific binding sites. For example, fusion proteins of the enveloped viruses have been shown to attach stearates exclusively to the cysteine located at the C-terminal end of the transmembrane domain, while cysteines in the cytoplasmic domain have been modified with palmitates. In addition, emerging evidence suggests that the covalently linked fatty acids in the viral fusion proteins could recruit cholesterol into the viral membrane. We termed this preferential attachment of fatty acid residues of different types to the specific sites, depending on their localization, as "differential" S-acylation. Furthermore, MALDI-TOF MS detected attachment of unsaturated fatty acids (oleates) to the GNAI protein in response to stearate supplementation, shifting this regulatory protein out of the detergent-resistant membranes (lipid rafts) and, consequently, exerting antitumor effect. Solving the first 3D-structures of DHHC acyltransferases allowed proposing a mechanism of different fatty acids selection. However, it remains unclear whether preference for the acyl chain length is determined by the structure of the enzyme, protein substrate, or by the lipid composition of the membrane. In this review, we summarize the latest advances in the study of protein S-acylation with different types of fatty acids and substantiate significance of this post-translational modification from both fundamental and practical perspectives.