Myristoylation is a modification where a myristoyl group, derived from myristic acid, attaches to a protein. This attachment occurs through a covalent amide bond to an N-terminal glycine residue. This process acts as a molecular anchor, directing proteins to specific cellular locations. It is a common type of fatty acylation found in various organisms, including animals, plants, fungi, and viruses.
The Biochemical Process of Myristoylation
Myristoylation involves myristic acid, a 14-carbon saturated fatty acid, being covalently added to a protein. This fatty acid is transferred from myristoyl-coenzyme A (CoA) to the target protein by N-myristoyltransferase (NMT). NMT facilitates the attachment of the myristoyl group to an N-terminal glycine residue.
In vertebrates, two isoforms of NMT, NMT1 and NMT2, carry out this modification. The process can occur co-translationally, happening as the protein is synthesized on ribosomes, following the removal of the initial methionine residue.
Myristoylation can also happen post-translationally. This occurs when an internal glycine residue is exposed after proteolytic cleavage, allowing the myristoyl group to be added to this newly exposed glycine.
Cellular Functions of Myristoylated Proteins
The addition of a myristoyl group to a protein significantly impacts its cellular behavior and localization. A primary function is membrane targeting, where the hydrophobic myristate tail inserts into the lipid bilayer. This acts as a tether, anchoring the protein to structures such as the plasma membrane, endoplasmic reticulum, or Golgi apparatus. This localization is important for the proper function of many proteins.
Myristoylated proteins also play a role in signal transduction pathways. By localizing proteins to specific membrane compartments, myristoylation brings signaling components into close proximity, enabling them to interact and relay messages efficiently. This allows for rapid cellular responses to various stimuli.
Myristoylation also mediates specific protein-protein interactions. The myristoyl group can interact with other proteins, contributing to the formation of protein complexes or modulating their activity.
Role in Health and Disease
Myristoylated proteins are involved in various health and disease contexts, often due to their membrane-targeting capabilities. Viruses like HIV hijack the host cell’s myristoylation machinery for their replication cycle. The HIV Gag polyprotein, which forms the structural core of new viral particles, requires myristoylation of its matrix protein domain to associate with the host cell membrane for assembly and budding. If this myristoylation is prevented, HIV particles are not released, and the virus loses its infectivity.
In cancer, myristoylated proteins can contribute to uncontrolled cell growth and proliferation. A well-known example is the Src kinase, an oncoprotein that, when myristoylated, localizes to the cell membrane. This membrane association is necessary for Src to promote cancerous signaling and cellular transformation. Elevated levels of N-myristoyltransferase (NMT) have been observed in certain cancers, including colon, gallbladder, and brain tumors, suggesting a reliance of cancer cells on this modification.
Myristoylation is also important for the viability and virulence of pathogenic fungi, such as Candida albicans. The myristoylation of proteins like ADP-ribosylation factor (Arf) in Candida albicans is necessary for its vegetative growth. A reduction in Arf myristoylation can lead to growth arrest and cell death in these fungi, indicating its importance for fungal survival and potential as a therapeutic target.
Therapeutic Applications and Research
Understanding the role of myristoylation in disease has opened avenues for therapeutic development. The enzyme N-myristoyltransferase (NMT) has emerged as a drug target due to its involvement in various pathological processes. Scientists are actively developing NMT inhibitors, which are molecules designed to block the enzyme’s activity.
These NMT inhibitors aim to disrupt the myristoylation process, thereby interfering with the function of myristoylated proteins that contribute to disease. For instance, NMT inhibitors are being explored as antiviral agents, particularly against viruses like HIV, by preventing the myristoylation of viral proteins like Gag. Such inhibitors could also serve as anticancer agents by disrupting the membrane localization and signaling of oncogenic myristoylated proteins such as Src.
NMT inhibitors also show promise as a new class of antifungal drugs. By targeting fungal NMT, these inhibitors can impair the viability and growth of pathogenic fungi like Candida albicans, which rely on myristoylation for survival. Research continues to identify and refine these inhibitors, seeking compounds with high selectivity for pathogen-specific NMTs over human NMTs to minimize side effects.