Abstract
Fatty acylation is a widespread form of protein modification that occurs on specific intracellular and secreted proteins. Beyond increasing hydrophobicity and the affinity of the modified protein for lipid bilayers, covalent attachment of a fatty acid exerts effects on protein localization, inter- and intramolecular interactions and signal transduction. As such, research into protein fatty acylation has been embraced by an extensive community of biologists. This special issue highlights advances at the forefront of the field, by focusing on two families of enzymes that catalyse post-translational protein fatty acylation, zDHHC palmitoyl acyltransferases and membrane-bound O-acyl transferases, and signalling pathways regulated by their fatty acylated protein substrates. The collected contributions catalogue the tremendous progress that has been made in enzyme and substrate identification. In addition, articles in this special issue provide insights into the pivotal functions of fatty acylated proteins in immune cell, insulin and EGF receptor-mediated signalling pathways. As selective inhibitors of protein fatty acyltransferases are generated, the future holds great promise for therapeutic targeting of fatty acyltransferases that play key roles in human disease.
Highlights
Covalent attachment of fatty acids to proteins is a form of lipid modification that occurs on thousands of proteins
The contributions are grouped into three subject areas: MBOATs, zDHHCs and signalling pathways regulated by S-palmitoylated proteins
Concluding remarks and future directions. The contributions in this special issue illustrate the breadth of impact that fatty acylation exerts on protein function
Summary
Covalent attachment of fatty acids to proteins is a form of lipid modification that occurs on thousands of proteins. The vast majority of protein fatty acylation occurs by thioester modification of cysteine residues with palmitate, a 16-carbon saturated fatty acid. These reactions, referred to as S-palmitoylation or S-acylation, are catalysed by the zDHHC family of palmitoyl acyltransferases (PATs). Hhat catalyses the attachment of palmitate to Hedgehog proteins, Porcn acylates Wnt proteins with palmitoleoate and GOAT links octanoate to the peptide hormone ghrelin. These reactions primarily occur on the luminal side of the ER membrane, the recent finding that GOAT resides at the plasma membrane allows for potential cellsurface re-acylation of ghrelin. The balance between acylation and deacylation reactions thereby fine-tunes signalling pathway dynamics
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