Myristoyl is a lipid modification derived from myristic acid, a 14-carbon saturated fatty acid. This group is covalently attached to proteins, typically at an N-terminal glycine residue, in a process called myristoylation. Myristoylation plays a role in membrane targeting, protein-protein interactions, and signal transduction pathways, regulating protein function and localization.
Understanding Myristoyl and Myristoylation
A myristoyl group is a fatty acid chain derived from myristic acid, a 14-carbon saturated fatty acid. It covalently attaches to proteins. The myristoyl group forms an amide bond with the alpha-amino group of an N-terminal glycine residue on the target protein.
The process of myristoylation is carried out by N-myristoyltransferases (NMTs). These enzymes catalyze the transfer of the myristoyl group from myristoyl-coenzyme A (CoA) to the protein. This attachment can occur in two ways: co-translationally, during protein synthesis, or post-translationally, after protein formation.
In co-translational myristoylation, the initiator methionine residue at the N-terminus of a newly forming protein is removed, exposing a glycine. NMT then recognizes this exposed glycine and attaches the myristoyl group. Post-translational myristoylation occurs when an internal glycine residue becomes exposed, often due to a proteolytic cleavage event. This modification is widespread, found in diverse life forms such as animals, plants, fungi, protozoans, and viruses.
Myristoyl’s Role in Cellular Function
Myristoylation has varied roles within cells. One primary function is directing proteins to cell membranes. The attached myristoyl group, being hydrophobic, allows proteins to insert into the lipid bilayer of membranes, such as the plasma membrane, endoplasmic reticulum, or mitochondria. This anchors proteins at specific cellular locations, enabling functions like signal reception or enzymatic reactions.
The myristoyl group also influences how proteins interact with each other. Myristoylation helps form functional complexes by facilitating protein-protein interactions. For example, the myristoyl group can be exposed or hidden within a protein, allowing for changes in protein conformation that affect its binding partners.
Myristoylation functions as a “molecular switch” in various signal transduction pathways. The ability of the myristoyl group to change its orientation, such as being exposed or sequestered within the protein, allows for precise control over protein activity and localization in response to signals. For instance, in some proteins, calcium binding can cause the myristoyl group to become exposed, enabling the protein to then bind to a membrane.
Myristoyl’s Influence on Health and Disease
Myristoylation influences human health and disease. In cancer, altered myristoylation or changes in myristoylated proteins can contribute to the growth and spread of cancerous cells. For instance, some myristoylated proteins are involved in signaling pathways that become abnormally active in cancer, promoting uncontrolled cell proliferation and survival. Research is exploring how targeting these aberrant myristoylation events could offer new strategies for cancer treatment.
Myristoylation also plays a part in the life cycles of certain viruses, impacting their ability to infect cells and replicate. For example, in viruses like HIV and poliovirus, myristoylated viral proteins are necessary for processes such as membrane association, viral assembly, or the transfer of viral genetic material into the host cell. Understanding these mechanisms could lead to the development of antiviral therapies that block myristoylation and thus inhibit viral propagation.
Furthermore, myristoylation is linked to apoptosis, which is the process of programmed cell death. Defects in apoptotic pathways are often observed in diseases like cancer, where cells fail to undergo proper programmed death. Myristoylated proteins, such as Bid, can translocate to mitochondria and induce the release of cytochrome C, a key step in initiating apoptosis.