Lipid Modification of Proteins: Targeting to Membranes

Abstract

Lipid modification encompasses the covalent linkage of three major classes of hydrophobic groups to proteins: fatty acids (myristate and/or palmitate), isoprenoids (farnesyl or geranylgeranyl), and glycosylphosphatidyl inositol (GPI) anchors. Attachment of each of these moieties regulates protein structure, intracellular localization, and function. Membrane interactions are essential for the function of many lipid-modified proteins. The nature of the modifying group determines the strength and specificity of membrane association. Proteins that are modified by myristate or farnesyl require a second signal, either a polybasic region or palmitate, to bind tightly to a membrane, whereas attachment of geranylgeranyl or a GPI anchor is sufficient for stable attachment to a lipid bilayer. Multiple types of mechanisms exist to allow lipid-modified proteins to undergo reversible membrane binding. Cycles of palmitoylation/depalmitoylation are operative for palmitoylated proteins, while myristoylated or farnesylated proteins use a switch mechanism to sequester the lipid group and promote release from the membrane. Lipid modification is also responsible for regulating protein trafficking throughout the cell and targeting proteins to specific subcellular organelles. Given the involvement of lipid-modified proteins in cancer and other disorders, drugs that inhibit lipid modification have the potential to be efficacious for treatment of human diseases.