Chapter 53 - Lipid-Mediated Localization of Signaling Proteins

Abstract

This chapter provides a description on the structures of the different lipid modifications and how lipids are attached to proteins. It also discusses how these modifications impact the localization of lipidated proteins. Numerous signaling proteins are modified with amide-linked myristate, including the Src family of non-receptor tyrosine kinases, members of the Gi family of G-protein α subunits, the catalytic subunit of protein kinase A, and the MARCKS protein, a protein kinase C substrate. Modification of the protein occurs co-translationally upon removal of the initiator methionine by methionylpeptidase. A number of cell surface proteins are anchored to the plasma membrane through a glycosylphosphatidylinositol (GPI). This lipid modification is composed of a phosphatidylinositol lipid connected through a carbohydrate linker to the C-terminal carboxyl group of a protein. Covalent lipid modifications promote membrane association by direct insertion of the fatty acid or isoprenoid into the lipid bilayer. However, N-myristoylated and prenylated proteins are found in the cytoplasm as well as on cellular membranes, whereas S-palmitoylated proteins appear to be exclusively associated with membranes. The most frequent lipid modification found on integral membrane proteins is palmitoylation of cysteine residues within the cytoplasmic domain(s). Integral membrane proteins do not require covalent lipid modifications for membrane attachment. Palmitoylation can influence the trafficking of integral membrane proteins through the endocytic pathway, such as endocytosis of the anthrax toxin receptor is regulated through two posttranslational modifications, palmitoylation and ubiquitination, which play opposing roles. Palmitoylation and ubiquitination of the anthrax toxin receptors occurs at cysteine residues within the cytoplasmic domain of the receptor. The consequence of mutating the palmitoylated cysteines to alanine appears to be premature targeting of the receptor to lysosomes.