Myristilation

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Myristoylated proteins[edit]
Protein Physiological Role Myristoylation Function

Post-translational myristoylation during

Actin Cytoskeleton structural protein
apoptosis [8]

Post-translational myristoylation after caspase

Bid Apoptosis promoting protein cleavage targets protein to mitochondrial
membrane[8]

actin cross-linking when

Co-translational myristoylation aids in plasma
MARCKS phosphorylated by protein kinase
membrane association
C

Co-translational myristoylation aids in plasma

G-Protein Signaling GTPase
membrane association[11]

Post-translational myristoylation up-regulates

Gelsolin Actin filament-severing protein
anti-apoptotic properties [8]

Post-translational myristoylation up-regulates

Serine/threonine kinase cell
PAK2 apoptotic properties and induces plasma
growth, mobility, survival stimulator
membrane localization[8]

vesicular trafficking and actin N-terminus myristoylation aids in membrane

Arf
remodeling regulation association

Hippocalcin Neuronal calcium sensor Contains a Ca2+/myristoyl switch

Signal transduction[edit]
Myristoylation plays a vital role in membrane targeting and signal transduction[15] 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. [16]

Apoptosis[edit]
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[edit]

Cancer[edit]
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][13][17] Activation of c-Src can lead to the
so-called hallmarks of cancer: upregulation of angiogenesis, proliferation, and invasion.[18]

Viral infectivity[edit]

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.[19] This myristoylation
modification targets gag to the membrane of the host cell. Utilizing the myristoyl-electrostatic switch,
[12]
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.[17] In order to prevent viral infectivity,
myristoylation of the matrix protein could become a good drug target.

Prokaryotic and eukaryotic infections[edit]

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]

References[edit]

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