Lipid-anchored proteins (also known as lipid-linked proteins) are proteins that are covalently attached to lipids embedded into biological membranes. The lipid-anchored protein can be located on either side of the cell membrane. Thus, the lipid serves to anchor the protein to the cell membrane. Such proteins are a type of proteolipids. The lipid groups contribute to the intracellular localization and the biological function of the protein to which they are attached. The lipid serves as a mediator of the protein association with specific biological membranes and protein-protein interactions. The lipidation can also sequester a protein away from its substrate to inactivate the protein and then activate it by substrate presentation. Overall, there are three main types of lipid-anchored proteins which include prenylated proteins, fatty acylated proteins and glycosylphosphatidylinositol-linked proteins (GPI). A protein can have multiple lipid groups covalently attached to specific amino acid residues.
Prenylated proteins
Prenylated proteins are proteins with covalently attached hydrophobic isoprene polymers (i.e. branched five-carbon hydrocarbon) at cysteine residues of the protein. More specifically, these isoprenoid groups, usually farnesyl (15-carbon) and geranylgeranyl (20-carbon) are attached to the protein via thioether linkages at cysteine residues near the C terminal of the protein. This prenylation of lipid chains to proteins facilitate their interaction with the cell membrane.
The prenylation motif "CaaX box" is the most common prenylation site in proteins, that is, the site where farnesyl or geranylgeranyl covalently attach. In the CaaX box sequence, the C represents the cysteine that is prenylated, the A represents any aliphatic amino acid and the X determines the type of prenylation that will occur. If the X is an Ala, Met, Ser or Gln the protein will be farnesylated via the farnesyltransferase enzyme and if the X is a Leu then the protein will be geranylgeranylated via the geranylgeranyltransferase I enzyme. Both of these enzymes are similar with each containing two subunits.
Roles and function
Prenylated proteins are particularly important for eukaryotic cell growth, differentiation and morphology. Furthermore, protein prenylation is a reversible post-translational modification to the cell membrane. This dynamic interaction of prenylated proteins with the cell membrane is important for their signalling functions and is often deregulated in disease processes such as cancer. More specifically, Ras is the protein that undergoes prenylation via farnesyltransferase and when it is switched on it can turn on genes involved in cell growth and differentiation. Thus overactiving Ras signalling can lead to cancer. An understanding of these prenylated proteins and their mechanisms have been important for the drug development efforts in combating cancer. Other prenylated proteins include members of the Rab and Rho families as well as lamins. Some important prenylation chains that are involved in the HMG-CoA reductase metabolic pathway are geranylgeraniol, farnesol and dolichol. These isoprene polymers (e.g. geranyl pyrophosphate and farnesyl pyrophosphate) are involved in the condensations via enzymes such as prenyltransferase that eventually cyclizes to form cholesterol.
Fatty acylated proteins Fatty acylated proteins are proteins that have been post-translationally modified to include the covalent attachment of fatty acids at certain amino acid residues. The most common fatty acids that are covalently attached to the protein are the saturated myristic (14-carbon) acid and palmitic acid (16-carbon). Proteins can be modified to contain either one or both of these fatty acids.
N-myristoylation N-myristoylation (i.e. attachment of myristic acid) is generally an irreversible protein modification that typically occurs during protein synthesis in which the myrisitc acid is attached to the α-amino group of an N-terminal glycine residue through an amide linkage. This reaction is facilitated by N-myristoyltransferase . These proteins usually begin with a Met-Gly sequence and with either a serine or threonine at position 5. Proteins that have been myristoylated are involved in signal transduction cascade, protein-protein interactions and in mechanisms that regulate protein targeting and function. An example in which the myristoylation of a protein is important is in apoptosis, programmed cell death. After the protein BH3 interacting-domain death agonist (Bid) has been myristoylated, it targets the protein to move to the mitochondrial membrane to release cytochrome c, which then ultimately leads to cell death. Other proteins that are myristoylated and involved in the regulation of apoptosis are actin and gelsolin.
S-palmitoylation
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