Fatty acylation of proteins: The long and the short of it

Abstract

Long, short and medium chain fatty acids are covalently attached to hundreds of proteins. Each fatty acid confers distinct biochemical properties, enabling fatty acylation to regulate intracellular trafficking, subcellular localization, protein-protein and protein-lipid interactions. Myristate and palmitate represent the most common fatty acid modifying groups. New insights into how fatty acylation reactions are catalyzed, and how fatty acylation regulates protein structure and function continue to emerge. Myristate is typically linked to an N-terminal glycine, but recent studies reveal that lysines can also be myristoylated. Enzymes that remove N-terminal myristoyl-glycine or myristate from lysines have now been identified. DHHC proteins catalyze S-palmitoylation, but the mechanisms that regulate substrate recognition by individual DHHC family members remain to be determined. New studies continue to reveal thioesterases that remove palmitate from S-acylated proteins. Another area of rapid expansion is fatty acylation of the secreted proteins Hedgehog, Wnt and Ghrelin, by Hhat, Porcupine and GOAT, respectively. Understanding how these membrane bound O-acyl transferases recognize their protein and fatty acyl CoA substrates is an active area of investigation, and is punctuated by the finding that these enzymes are potential drug targets in human diseases.

Photoactivatable Myristic Acid Probes for UNC119‐Cargo Interactions

“…Furthermore, protein myristoylation is essential for parasite morphology and viability in protozoan parasites, including Leishmania and Trypanosoma brucei , and in Plasmodium species, which are the causative agents of malaria . The myristate moiety is involved in various biological processes, including protein–lipid and protein–protein interactions, membrane binding and activation . However, in many cases, the exact mechanism underlying these processes is not completely understood, and therefore, the development of specific molecular probes that can assist in identifying key interactions involving the myristate moiety is of considerable interest.…”

Single-cell Wnt signaling niches maintain stemness of alveolar type 2 cells

“…Neighboring fibroblasts were an excellent candidate for the source because some share intimate physical connections with AT2 cells (28), such as Pdgfrα-expressing 'lipofibroblasts' that support their production of surfactant and formation of alveolospheres in culture (17, 29, 30). Indeed, we found that the transmembrane protein Porcupine (Porcn), which catalyzes fatty acylation of Wnts and promotes their secretion (31) and is a putative marker of Wnt signaling niches (32), was expressed in rare alveolar stromal cells (Fig. 2a), most of which were Pdgfrα -expressing fibroblasts (Fig.…”

Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform

“…Numerous CoA thioesters are also involved in the post-translational modification of histones and thousands of other proteins (1)(2)(3)(4)(5). Three major subcellular CoA pools are found in the cytosol, mitochondria, and peroxisomes to support specific metabolic pathways (6,7).…”