Chemical-proteomics profiling of reactive cysteines near a hydrophobic pocket

This project investigates reactive cysteine residues located near hydrophobic pockets in proteins, features conserved in autopalmitoylated proteins. S-palmitoylation is a post-translational modification that regulates protein localization and function, and has been implicated in neurological, metabolic, infectious, and cancer-related processes. Autopalmitoylation occurs through a thioester transfer from palmitoyl-CoA to nucleophilic cysteine residues, a reaction that can be facilitated by structural or adaptor proteins with enzyme-like activities. In this study, chemical-proteomics approaches were applied to map reactive cysteines positioned adjacent to hydrophobic pockets that may serve as ligandable sites. These datasets enable the identification of druggable microenvironments in autopalmitoylated or other lipid-modified proteins, providing a resource for studying the mechanistic basis and therapeutic potential of palmitoylation-dependent regulation.