Protein N-Myristoylation

Various lipids and lipid metabolites bind to and modify proteins in eukaryotic cells, which is termed "protein lipidation." There are four main types of protein lipidation, including myristoylation, glycosylphosphatidylinositol anchoring, palmitoylation, and prenylation. Myristoylation, as an important post-translational modification (PTM), involves attaching myristic acid molecules to the N-terminal glycine residues of specific proteins and affects their physiological properties, such as plasma targeting, subcellular tracking and localization, thereby affecting protein function. N-myristoylation is gaining increasing attention in the field of human diseases due to the identification of novel pathogenic N-myristoylated proteins. This PTM has been implicated in a wide range of conditions, including infectious diseases, parasitic diseases, and cancer.

Mechanism of Protein N-Myristoylation

The mechanism of N-myristoylation involves a series of enzymatic reactions that attach a myristoyl group, derived from myristic acid, to the alpha-amino group of an N-terminal glycine residue of specific proteins. The process of myristoylation can occur either co-translationally or post-translationally, depending on the timing of the addition of the myristoyl group to the protein.

Co-translational myristoylation

Co-translational myristoylation refers to the addition of the myristoyl group to the protein during the process of protein synthesis. The myristoyl group is attached to the nascent protein chain shortly after the initiator methionine residue is removed. The co-translational myristoylation mechanism involves the following steps:

• Initiation of protein synthesis: The ribosome initiates protein synthesis by binding to the mRNA and recruiting the initiator tRNA, which carries the initiator methionine.
• Methionine removal: In many cases, the initiator methionine residue is cotranslationally cleaved by a specific methionine aminopeptidase. This exposes the glycine residue at the N-terminus of the protein.
• Myristoylation: N-myristoyltransferase (NMT), the enzyme responsible for myristoylation, recognizes the exposed N-terminal glycine residue of the nascent protein chain. The myristoyl group, derived from myristoyl-CoA, is transferred to the glycine residue, forming an amide bond. This covalently attaches the myristoyl group to the protein.

Post-translational myristoylation

Post-translational myristoylation occurs after the protein has been fully synthesized, folded, and released from the ribosome. The myristoylation of the protein takes place in the cytoplasm or in specific compartments of the cell. The post-translational myristoylation mechanism involves the following steps:

• Protein synthesis and folding: The protein is synthesized on the ribosome and then undergoes proper folding to adopt its functional conformation.
• Exposure of the glycine residue: In certain cases, post-translational modifications or proteolytic cleavage events expose an internal glycine residue in the protein. This glycine residue becomes available for myristoylation.
• Myristoylation: NMT recognizes the exposed internal glycine residue in the protein and catalyzes the transfer of the myristoyl group from myristoyl-CoA to the glycine residue, forming an amide bond.

Co-translational myristoylation and post-translational myristoylation both result in the covalent attachment of the myristoyl group to the protein. The timing of myristoylation can have functional implications, as co-translational myristoylation allows for immediate membrane targeting and localization of the nascent protein, while post-translational myristoylation can regulate protein activity or localization in response to specific cellular signals or conditions.

Figure 1. The molecular mechanism of protein N-myristoylation catalyzed by N-myristoyltransferase (NMT).
(Source: Wang, B. et al., 2021)

Dual Modifications of Myristoylated Proteins

Dual modifications of myristoylated proteins refer to the presence of additional PTMs occurring in conjunction with protein N-myristoylation. These dual modifications can further modulate protein function, localization, stability, and interactions, adding an extra layer of complexity to the regulation of myristoylated proteins. Some common examples of dual modifications in myristoylated proteins include:

• Palmitoylation: Palmitoylation is the attachment of a palmitoyl group, a 16-carbon saturated fatty acid, to cysteine residues within a protein. It often occurs in proteins that are also myristoylated. Dual myristoylation-palmitoylation modifications have been observed in several proteins, including members of the Src family kinases, G proteins, and Ras superfamily proteins. Palmitoylation can further enhance protein membrane association and modulate protein-protein interactions beyond the effects of myristoylation alone.
• Phosphorylation: Protein myristoylation is often followed by phosphorylation of nearby residues. This additional phosphorylation can have an impact on the interaction of the myristoylated protein with cellular membranes. Specifically, it decreases the electrostatic affinity of the protein for the membrane. As a result, the myristoylated protein can dissociate from the membrane and translocate to the cytoplasm.

For research use only, not for use in diagnostic procedures.

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