Myristoylation

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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.

Myristoylation is a lipidation modification where a

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.

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

The enzyme N-myristoyltransferase (NMT) or

NMT2, both of which are members of the GCN5 acetyltransferase superfamily.[8]

Structure

The

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

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.

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

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

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

Myristoylation molecular switch

Positive (basic) residues on the protein interact with negatively charged phospholipids on the membrane stabilizing myristoyl-dependent membrane association.
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

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

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

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

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

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.

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

African sleeping sickness.[8]

See also

References

  1. ^
    ISBN 978-0716743392.{{cite book}}: CS1 maint: multiple names: authors list (link
    )
  2. ^
    ISBN 978-0-12-122722-7
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  3. PMID 30501005
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  4. PMID 3278984
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  5. ^
    PMID 11527981
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  6. ^
    PMID 6959104
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  7. ^
    S2CID 40889752
    .
  8. ^
    PMID 21056615
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  9. ^
    PMID 10570244
    .
  10. ^ Snider, Jared. "Overview of Post-Translational Modifications (PTMs)". Thermo Scientific.
  11. PMID 11313912.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  12. S2CID 204833583
    .
  13. ^
    PMID 7667880
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  14. ^
    PMID 19898886
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  15. PMID 20583817
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  16. PMID 20467215
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  17. PMID 8521505
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  18. ^
    PMID 2545855
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  19. PMID 21376230
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  20. PMID 17411366
    .

External links
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