Lipid modifications of proteins

Lipid modifications of proteins (Fig. 1) are widespread and functionally important in eukaryotic cells. For example, many intracellular proteins such as the signal-transducing heterotrimeric GTP-binding proteins (G proteins) and the Ras superfamily of G proteins are modified by 14or 16-carbon fatty acids and/or 15or 20-carbon isoprenoids. Also, a variety of cell surface proteins such as acetylcholinesterase, the T lymphocyte surface antigen Thy-1, and members of the cell adhesion protein family are modified by glycosylphosphatidylinositol (GPI) anchors. In most cases, the lipid moiety is crucial to protein function as it allows an otherwise water-soluble protein to interact strongly with membranes. The lipid moiety may also aid in the sorting of the protein to membrane domains that promote lateral and transbilayer protein-protein interactions that are critical for cell function. In some instances, the covalent lipid acts as a functional switch resulting in functional membrane association of certain protein conformations but not of others. The covalent attachment of lipid to protein was first described in a study of myelin protein in 1951, but only clearly documented as important for protein biosynthesis and function in a study of the outer membrane murein lipoprotein of Escherichia coli by Braun and Rehn in 1969. These early discoveries were followed, in the 1970s, by the identification of fatty acids linked to viral glycoproteins and of isoprenoids covalently attached to fungal mating factors and to GTP-binding proteins. The 1980s saw the identification and characterization of N-myristoylated proteins and GPI-anchored proteins, and work on tissue patterning factors in the 1990s revealed a new class of autoprocessed proteins modified by cholesterol. Our purpose in this chapter is to document the structure of these various lipid modifications, describe their biosynthesis, and survey their functional significance. The chapter does not cover the structure and biosynthesis of diacylglycerol-modified proteins found in E. coli and other bacteria; information on this may be found in articles by Wu and colleagues (Wu, 1993).