Lipidmodification

Lipid modification, or lipidation, is the covalent attachment of lipid groups to biomolecules, most commonly proteins. This process increases hydrophobicity, promotes membrane association, and influences subcellular localization, trafficking, stability, and signaling. Lipidation is essential for the proper function of many signaling proteins, receptors, and secreted factors.

The major forms of lipid modification in proteins include: N-myristoylation, in which a myristoyl group is attached to the N-terminal glycine of a polypeptide, typically cotranslationally; S-palmitoylation, a reversible thioester linkage of palmitate to cysteine residues catalyzed by DHHC palmitoyltransferases, dynamically regulating membrane binding and trafficking; prenylation, the addition of farnesyl or geranylgeranyl groups to a cysteine near the C-terminus within a CAAX motif, often followed by proteolysis and methylation to target proteins to membranes; and the attachment of a glycosylphosphatidylinositol (GPI) anchor to the C-terminus of a protein, tethering it to the outer leaflet of the plasma membrane. In bacteria, lipoproteins acquire diacylglycerol anchors at an N-terminal cysteine after signal peptide cleavage, anchoring them to membranes.

Other lipidations include cholesterol modification for a subset of secreted and membrane-associated proteins, such as Hedgehog family members. Lipid modifications can be irreversible or reversible and are mediated by specific enzymes, offering opportunities for regulation and therapeutic targeting. Detection and study employ biochemical methods, metabolic labeling, and lipidomics approaches to understand localization, interactions, and function in health and disease.