Myristoylation

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In myristoylation, a myristoyl group (derived from myristic acid, pictured above) is added. Myristic acid.svg
In myristoylation, a myristoyl group (derived from myristic acid, pictured above) is added.
Co-translational addition of myristic acid by N-myristoyltransferase to N-terminal glycine of a nascent protein. Co- and Post-Translational Myristoylation.png
Co-translational addition of myristic acid by N-myristoyltransferase to N-terminal glycine of a nascent protein.

Myristoylation is a lipidation modification where a myristoyl group, derived from myristic acid, is covalently attached by an amide bond to the alpha-amino group of an N-terminal glycine residue. [1] Myristic acid is a 14-carbon saturated fatty acid (14:0) with the systematic name of n-tetradecanoic acid. This modification can be added either co-translationally or post-translationally. N-myristoyltransferase (NMT) catalyzes the myristic acid addition reaction in the cytoplasm of cells. [2] This lipidation event is the most common type of fatty acylation [3] and is present in many organisms, including animals, plants, fungi, protozoans [4] and viruses. Myristoylation allows for weak protein–protein and protein–lipid interactions [5] and plays an essential role in membrane targeting, protein–protein interactions and functions widely in a variety of signal transduction pathways.

Contents

Discovery

In 1982, Koiti Titani's lab identified an "N-terminal blocking group" on the catalytic subunit of cyclic AMP-dependent protein kinase in cows as n-tetradecanoyl. [6] Almost simultaneously in Claude B. Klee's lab, this same N-terminal blocking group was further characterized as myristic acid. [7] Both labs made this discovery utilizing similar techniques: mass spectrometry and gas chromatography. [6] [7]

N-myristoyltransferase

Crystal structure of human type-I N-myristoyltransferase with bound myristoyl-CoA. Myristoyl-CoA (red). PDB ID: 3IU1 N-Myristoyltransferase Subunit Bound to Myristoyl-CoA.png
Crystal structure of human type-I N-myristoyltransferase with bound myristoyl-CoA. Myristoyl-CoA (red). PDB ID: 3IU1

The enzyme N-myristoyltransferase (NMT) or glycylpeptide N-tetradecanoyltransferase is responsible for the irreversible addition of a myristoyl group to N-terminal or internal glycine residues of proteins. This modification can occur co-translationally or post-translationally. In vertebrates, this modification is carried about by two NMTs, NMT1 and NMT2, both of which are members of the GCN5 acetyltransferase superfamily. [8]

Structure

The crystal structure of NMT reveals two identical subunits, each with its own myristoyl CoA binding site. Each subunit consists of a large saddle-shaped β-sheet surrounded by α-helices. The symmetry of the fold is pseudo twofold.[ clarification needed ] Myristoyl CoA binds at the N-terminal portion, while the C-terminal end binds the protein. [9]

Mechanism

The addition of the myristoyl group proceeds via a nucleophilic addition-elimination reaction. First, myristoyl coenzyme A (CoA) is positioned in its binding pocket of NMT so that the carbonyl faces two amino acid residues, phenylalanine 170 and leucine 171. [9] This polarizes the carbonyl so that there is a net positive charge on the carbon, making it susceptible to nucleophilic attack by the glycine residue of the protein to be modified. When myristoyl CoA binds, NMT reorients to allow binding of the peptide. The C-terminus of NMT then acts as a general base to deprotonate the NH3+, activating the amino group to attack at the carbonyl group of myristoyl-CoA. The resulting tetrahedral intermediate is stabilized by the interaction between a positively charged oxyanion hole and the negatively charged alkoxide anion. Free CoA is then released, causing a conformational change in the enzyme that allows the release of the myristoylated peptide. [2]

Myristoylation addition mechanism by N-myristoyltransferase. Myristoylation mechanism.jpg
Myristoylation addition mechanism by N-myristoyltransferase.

Co-translational vs. post-translational addition

Co-translational and post-translational covalent modifications enable proteins to develop higher levels of complexity in cellular function, further adding diversity to the proteome. [10] The addition of myristoyl-CoA to a protein can occur during protein translation or after. During co-translational addition of the myristoyl group, the N-terminal glycine is modified following cleavage of the N-terminal methionine residue in the newly forming, growing polypeptide. [1] Post-translational myristoylation typically occurs following a caspase cleavage event, resulting in the exposure of an internal glycine residue, which is then available for myristic acid addition. [8]

Functions

Myristoylated proteins

ProteinPhysiological RoleMyristoylation Function
Actin Cytoskeleton structural proteinPost-translational myristoylation during apoptosis [8]
Bid Apoptosis promoting proteinPost-translational myristoylation after caspase cleavage targets protein to mitochondrial membrane [8]
MARCKS actin cross-linking when phosphorylated by protein kinase CCo-translational myristoylation aids in plasma membrane association
G-Protein Signaling GTPase Co-translational myristoylation aids in plasma membrane association [11]
Gelsolin Actin filament-severing proteinPost-translational myristoylation up-regulates anti-apoptotic properties [8]
PAK2 Serine/threonine kinase cell growth, mobility, survival stimulatorPost-translational myristoylation up-regulates apoptotic properties and induces plasma membrane localization [8]
Arf vesicular trafficking and actin remodeling regulationN-terminus myristoylation aids in membrane association
Hippocalcin Neuronal calcium sensor Contains a Ca2+/myristoyl switch
FSP1Apoptosis-inducing factor mitochondria-associated 2 (AIFM2)Facilitates the association of FSP1 with the lipid-bilayer which enables ferroptosis resistance. [12]

Myristoylation molecular switch

Myristoylelectrostaticswitch.jpg
Positive (basic) residues on the protein interact with negatively charged phospholipids on the membrane stabilizing myristoyl-dependent membrane association.
Myristoylligandswitch.jpg
Upon ligand binding to a myristoylated protein, the myristoyl group is exposed and available to associate with the membrane.

Myristoylation not only diversifies the function of a protein, but also adds layers of regulation to it. One of the most common functions of the myristoyl group is in membrane association and cellular localization of the modified protein. Though the myristoyl group is added onto the end of the protein, in some cases it is sequestered within hydrophobic regions of the protein rather than solvent exposed. [5] By regulating the orientation of the myristoyl group, these processes can be highly coordinated and closely controlled. Myristoylation is thus a form of "molecular switch." [13]

Both hydrophobic myristoyl groups and "basic patches" (highly positive regions on the protein) characterize myristoyl-electrostatic switches. The basic patch allows for favorable electrostatic interactions to occur between the negatively charged phospholipid heads of the membrane and the positive surface of the associating protein. This allows tighter association and directed localization of proteins. [5]

Myristoyl-conformational switches can come in several forms. Ligand binding to a myristoylated protein with its myristoyl group sequestered can cause a conformational change in the protein, resulting in exposure of the myristoyl group. Similarly, some myristoylated proteins are activated not by a designated ligand, but by the exchange of GDP for GTP by guanine nucleotide exchange factors in the cell. Once GTP is bound to the myristoylated protein, it becomes activated, exposing the myristoyl group. These conformational switches can be utilized as a signal for cellular localization, membrane-protein, and protein–protein interactions. [5] [13] [14]

Dual modifications of myristoylated proteins

Further modifications on N-myristoylated proteins can add another level of regulation for myristoylated protein. Dual acylation can facilitate more tightly regulated protein localization, specifically targeting proteins to lipid rafts at membranes [15] or allowing dissociation of myristoylated proteins from membranes.

Myristoylation and palmitoylation are commonly coupled modifications. Myristoylation alone can promote transient membrane interactions [5] that enable proteins to anchor to membranes but dissociate easily. Further palmitoylation allows for tighter anchoring and slower dissociation from membranes when required by the cell. This specific dual modification is important for G protein-coupled receptor pathways and is referred to as the dual fatty acylation switch. [5] [8]

Myristoylation is often followed by phosphorylation of nearby residues. Additional phosphorylation of the same protein can decrease the electrostatic affinity of the myristoylated protein for the membrane, causing translocation of that protein to the cytoplasm following dissociation from the membrane. [5]

Signal transduction

Myristoylation plays a vital role in membrane targeting and signal transduction [16] in plant responses to environmental stress. In addition, in signal transduction via G protein, palmitoylation of the α subunit, prenylation of the γ subunit, and myristoylation is involved in tethering the G protein to the inner surface of the plasma membrane so that the G protein can interact with its receptor. [17]

Apoptosis

Myristoylation is an integral part of apoptosis, or programmed cell death. Apoptosis is necessary for cell homeostasis and occurs when cells are under stress such as hypoxia or DNA damage. Apoptosis can proceed by either mitochondrial or receptor mediated activation. In receptor mediated apoptosis, apoptotic pathways are triggered when the cell binds a death receptor. In one such case, death receptor binding initiates the formation of the death-inducing signaling complex, a complex composed of numerous proteins including several caspases, including caspase 3. Caspase 3 cleaves a number of proteins that are subsequently myristoylated by NMT. The pro-apoptotic BH3-interacting domain death agonist (Bid) is one such protein that once myristoylated, translocates to the mitochondria where it prompts the release of cytochrome c leading to cell death. [8] Actin, gelsolin and p21-activated kinase 2 PAK2 are three other proteins that are myristoylated following cleavage by caspase 3, which leads to either the up-regulation or down-regulation of apoptosis. [8]

Impact on human health

Cancer

c-Src is a gene that codes for proto-oncogene tyrosine-protein kinase Src, a protein important for normal mitotic cycling. It is phosphorylated and dephosphorylated to turn signaling on and off. Proto-oncogene tyrosine-protein kinase Src must be localized to the plasma membrane in order to phosphorylate other downstream targets; myristoylation is responsible for this membrane targeting event. Increased myristoylation of c-Src can lead to enhanced cell proliferation and be responsible for transforming normal cells into cancer cells. [5] [14] [18] Activation of c-Src can lead to the so-called "hallmarks of cancer", among them upregulation of angiogenesis, proliferation, and invasion. [19]

Viral infectivity

HIV-1 utilizes myristoylation on the Matrix protein to target the viral proteins and viral genome to the membrane for budding and viral maturation. Viralassemblyhiv.jpg
HIV-1 utilizes myristoylation on the Matrix protein to target the viral proteins and viral genome to the membrane for budding and viral maturation.

HIV-1 is a retrovirus that relies on myristoylation of one of its structural proteins in order to successfully package its genome, assemble and mature into a new infectious particle. Viral matrix protein, the N-terminal–most domain of the gag polyprotein, is myristoylated. [20] This myristoylation modification targets gag to the membrane of the host cell. Utilizing the myristoyl-electrostatic switch, [13] including a basic patch on the matrix protein, gag can assemble at lipid rafts at the plasma membrane for viral assembly, budding and further maturation. [18] In order to prevent viral infectivity, myristoylation of the matrix protein could become a good drug target.

Prokaryotic and eukaryotic infections

Certain NMTs are therapeutic targets for development of drugs against bacterial infections. Myristoylation has been shown to be necessary for the survival of a number of disease-causing fungi, among them C. albicans and C. neoformans . In addition to prokaryotic bacteria, the NMTs of numerous disease-causing eukaryotic organisms have been identified as drug targets as well. Proper NMT functioning in the protozoa Leishmania major and Leishmania donovani (leishmaniasis), Trypanosoma brucei (African sleeping sickness), and P. falciparum (malaria) is necessary for survival of the parasites. Inhibitors of these organisms are under current investigation. A pyrazole sulfonamide inhibitor has been identified that selectively binds T. brucei, competing for the peptide binding site, thus inhibiting enzymatic activity and eliminating the parasite from the bloodstream of mice with African sleeping sickness. [8]

See also

Related Research Articles

<span class="mw-page-title-main">Protein primary structure</span> Linear sequence of amino acids in a peptide or protein

Protein primary structure is the linear sequence of amino acids in a peptide or protein. By convention, the primary structure of a protein is reported starting from the amino-terminal (N) end to the carboxyl-terminal (C) end. Protein biosynthesis is most commonly performed by ribosomes in cells. Peptides can also be synthesized in the laboratory. Protein primary structures can be directly sequenced, or inferred from DNA sequences.

<span class="mw-page-title-main">Post-translational modification</span> Chemical changes in proteins following their translation from mRNA

In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones.

<span class="mw-page-title-main">Peripheral membrane protein</span> Membrane proteins that adhere temporarily to membranes with which they are associated

Peripheral membrane proteins, or extrinsic membrane proteins, are membrane proteins that adhere only temporarily to the biological membrane with which they are associated. These proteins attach to integral membrane proteins, or penetrate the peripheral regions of the lipid bilayer. The regulatory protein subunits of many ion channels and transmembrane receptors, for example, may be defined as peripheral membrane proteins. In contrast to integral membrane proteins, peripheral membrane proteins tend to collect in the water-soluble component, or fraction, of all the proteins extracted during a protein purification procedure. Proteins with GPI anchors are an exception to this rule and can have purification properties similar to those of integral membrane proteins.

<span class="mw-page-title-main">Lipid-anchored protein</span> Membrane protein

Lipid-anchored proteins are proteins located on the surface of the cell membrane that are covalently attached to lipids embedded within the cell membrane. These proteins insert and assume a place in the bilayer structure of the membrane alongside the similar fatty acid tails. 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. They are a type of proteolipids.

The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amine group is bonded to the carboxylic group of another amino acid, making it a chain. That leaves a free carboxylic group at one end of the peptide, called the C-terminus, and a free amine group on the other end called the N-terminus. By convention, peptide sequences are written N-terminus to C-terminus, left to right (in LTR writing systems). This correlates the translation direction to the text direction, because when a protein is translated from messenger RNA, it is created from the N-terminus to the C-terminus, as amino acids are added to the carboxyl end of the protein.

In chemistry, acylation is a broad class of chemical reactions in which an acyl group is added to a substrate. The compound providing the acyl group is called the acylating agent. The substrate to be acylated and the product include the following:

<span class="mw-page-title-main">Prenylation</span> Addition of hydrophobic moieties to proteins or other biomolecules

Prenylation is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to lipid anchors like the GPI anchor, though direct evidence of this has not been observed. Prenyl groups have been shown to be important for protein–protein binding through specialized prenyl-binding domains.

<span class="mw-page-title-main">Hemagglutinin esterase</span> Glycoprotein present in some enveloped viruses

Hemagglutinin esterase (HEs) is a glycoprotein that certain enveloped viruses possess and use as an invading mechanism. HEs helps in the attachment and destruction of certain sialic acid receptors that are found on the host cell surface. Viruses that possess HEs include influenza C virus, toroviruses, and coronaviruses of the subgenus Embecovirus. HEs is a dimer transmembrane protein consisting of two monomers, each monomer is made of three domains. The three domains are: membrane fusion, esterase, and receptor binding domains.

Chemical modification refers to a number of various processes involving the alteration of the chemical constitution or structure of molecules.

<span class="mw-page-title-main">Palmitoylation</span>

Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine (S-palmitoylation) and less frequently to serine and threonine (O-palmitoylation) residues of proteins, which are typically membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their membrane association. Palmitoylation also appears to play a significant role in subcellular trafficking of proteins between membrane compartments, as well as in modulating protein–protein interactions. In contrast to prenylation and myristoylation, palmitoylation is usually reversible (because the bond between palmitic acid and protein is often a thioester bond). The reverse reaction in mammalian cells is catalyzed by acyl-protein thioesterases (APTs) in the cytosol and palmitoyl protein thioesterases in lysosomes. Because palmitoylation is a dynamic, post-translational process, it is believed to be employed by the cell to alter the subcellular localization, protein–protein interactions, or binding capacities of a protein.

Group-specific antigen, or gag, is the polyprotein that contains the core structural proteins of an Ortervirus. It was named as such because scientists used to believe it was antigenic. Now it is known that it makes up the inner shell, not the envelope exposed outside. It makes up all the structural units of viral conformation and provides supportive framework for mature virion.

<span class="mw-page-title-main">Glycylpeptide N-tetradecanoyltransferase 2</span> Protein-coding gene in the species Homo sapiens

Glycylpeptide N-tetradecanoyltransferase 2 known also as N-myristoyltransferase, is an enzyme that in humans is encoded by the NMT2 gene.

<span class="mw-page-title-main">Glycylpeptide N-tetradecanoyltransferase</span>

In enzymology, a glycylpeptide N-tetradecanoyltransferase is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Glycylpeptide N-tetradecanoyltransferase 1</span> Protein-coding gene in the species Homo sapiens

Glycylpeptide N-tetradecanoyltransferase 1 also known as myristoyl-CoA:protein N-myristoyltransferase 1 (NMT-1) is an enzyme that in humans is encoded by the NMT1 gene. It belongs to the protein N-terminal methyltransferase and glycylpeptide N-tetradecanoyltransferase family of enzymes.

<span class="mw-page-title-main">MARCKS</span> Protein-coding gene in the species Homo sapiens

Myristoylated alanine-rich C-kinase substrate is a protein that in humans is encoded by the MARCKS gene. It plays important roles in cell shape, cell motility, secretion, transmembrane transport, regulation of the cell cycle, and neural development. Recently, MARCKS has been implicated in the exocytosis of a number of vesicles and granules such as mucin and chromaffin. It is also the name of a protein family, of which MARCKS is the most studied member. They are intrinsically disordered proteins, with an acidic pH, with high proportions of alanine, glycine, proline, and glutamic acid. They are membrane-bound through a lipid anchor at the N-terminus, and a polybasic domain in the middle. They are regulated by Ca2+/calmodulin and protein kinase C. In their unphosphorylated form, they bind to actin filaments, causing them to crosslink, and sequester acidic membrane phospholipids such as PIP2.

BAALC is a gene that codes for the brain and acute leukemia cytoplasmic protein. The official symbol (BAALC) and official name is maintained by the HGNC. The function of BAALC is not fully understood yet, but has been suggested to have synaptic roles involving the post synaptic lipid raft. Lipid rafts are microdomains that are enriched with cholesterol and sphingolipids, lipid raft functions include membrane trafficking, signal processing, and regulation of the actin cytoskeleton. The postsynaptic lipid raft possesses many proteins and is one of the major sites for signal processing and postsynaptic density (PSD). Along with its involvement in the post synaptic lipid rafts, BAALC expression has been associated with Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia.

Src kinase family is a family of non-receptor tyrosine kinases that includes nine members: Src, Yes, Fyn, and Fgr, forming the SrcA subfamily, Lck, Hck, Blk, and Lyn in the SrcB subfamily, and Frk in its own subfamily. Frk has homologs in invertebrates such as flies and worms, and Src homologs exist in organisms as diverse as unicellular choanoflagellates, but the SrcA and SrcB subfamilies are specific to vertebrates. Src family kinases contain six conserved domains: a N-terminal myristoylated segment, a SH2 domain, a SH3 domain, a linker region, a tyrosine kinase domain, and C-terminal tail.

Protein methylation is a type of post-translational modification featuring the addition of methyl groups to proteins. It can occur on the nitrogen-containing side-chains of arginine and lysine, but also at the amino- and carboxy-termini of a number of different proteins. In biology, methyltransferases catalyze the methylation process, activated primarily by S-adenosylmethionine. Protein methylation has been most studied in histones, where the transfer of methyl groups from S-adenosyl methionine is catalyzed by histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

A proteolipid is a protein covalently linked to lipid molecules, which can be fatty acids, isoprenoids or sterols. The process of such a linkage is known as protein lipidation, and falls into the wider category of acylation and post-translational modification. Proteolipids are abundant in brain tissue, and are also present in many other animal and plant tissues. They include ghrelin, a peptide hormone associated with feeding. Many proteolipids are composed of proteins covalenently bound to fatty acid chains, often granting them an interface for interacting with biological membranes. They are not to be confused with lipoproteins, a kind of spherical assembly made up of many molecules of lipids and some apolipoproteins.

<i>O</i>-Octadecylhydroxylamine Chemical compound

O-Octadecylhydroxylamine (ODHA) is a white solid organic compound with the formula C18H39NO. ODHA is a noncanonical lipid, which contains a saturated alkyl tail and an aminooxy headgroup. This noncanonical lipid can be site selectively appended to the N-terminal of desired biopolymers such as peptides. ODHA drives the supramolecular assembly of modified protein, presumably through the hydrophobic collapse of ODHA chains.

References

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