Lipid-anchored protein

Prenylation chains (e.g. geranyl pyrophosphate)

Prenylated proteins are particularly important for eukaryotic cell growth, differentiation and morphology.[7] 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.[8] 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.[9] An understanding of these prenylated proteins and their mechanisms have been important for the drug development efforts in combating cancer.[10] Other prenylated proteins include members of the Rab and Rho families as well as lamins.[7]

Some important prenylation chains that are involved in the HMG-CoA reductase metabolic pathway[1] 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.[2]

N-myristoylation (i.e. attachment of myristic acid) is generally an irreversible protein modification that typically occurs during protein synthesis[11][13] in which the myrisitc acid is attached to the α-amino group of an N-terminal glycine residue through an amide linkage.[2][12] 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.[11] Proteins that have been myristoylated are involved in signal transduction cascade, protein-protein interactions and in mechanisms that regulate protein targeting and function.[13] 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.[14] Other proteins that are myristoylated and involved in the regulation of apoptosis are actin and gelsolin.

Palmitoylation

S-palmitoylation (i.e. attachment of palmitic acid) is a reversible protein modification in which a palmitic acid is attached to a specific cysteine residue via thioester linkage.[2][11] The term S-acylation can also be used when other medium and long fatty acids chains are also attached to palmitoylated proteins. No consensus sequence for protein palmitoylation has been identified.[11] Palmitoylated proteins are mainly found on the cytoplasmic side of the plasma membrane where they play a role in transmembrane signaling. The palmitoyl group can be removed by palmitoyl thioesterases. It is believed that this reverse palmitoylation may regulate the interaction of the protein with the membrane and thus have a role in signaling processes.[2] Furthermore, this allows for the regulation of protein subcellular localization, stability and trafficking.[15] An example in which palmitoylation of a protein plays a role in cell signaling pathways is in the clustering of proteins in the synapse. When the postsynaptic density protein 95 (PSD-95) is palmitoylated, it is restricted to the membrane and allows it to bind to and cluster ion channels in the postsynaptic membrane. Thus, palmitoylation can play a role in the regulation of neurotransmitter release.[16]

Palmitoylation mediates the affinity of a protein for lipid rafts and facilitates the clustering of proteins.[17] The clustering can increase the proximity of two molecules. Alternatively, clustering can sequester a protein away from a substrate. For example, palmitoylation of phospholipase D (PLD) sequesters the enzyme away from its substrate phosphatidylcholine. When cholesterol levels decrease or PIP2 levels increase the palmitate mediated localization is disrupted, the enzyme trafficks to PIP2 where it encounters its substrate and is active by substrate presentation.[18][19][20]

The sugar residues in the tetrasaccaride and the fatty acid residues in the phosphatidylinositol group vary depending on the protein.[2] This great diversity is what allows the GPI proteins to have a wide range of functions including acting as hydrolytic enzymes, adhesion molecule, receptors, protease inhibitor and complement regulatory proteins.[24] Furthermore, GPI proteins play an important in embryogenesis, development, neurogenesis, the immune system and fertilization.[21] More specifically, the GPI protein IZUMO1R (also named JUNO after the Roman goddess of fertility) on the egg plasma has an essential role in sperm-egg fusion. Releasing the IZUMO1R (JUNO) GPI protein from the egg plasma membrane does not allow for sperm to fuse with the egg and it is suggested that this mechanism may contribute to the polyspermy block at the plasma membrane in eggs.[25] Other roles that GPI modification allows for is in the association with membrane microdomains, transient homodimerization or in apical sorting in polarized cells.[21]