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N-myristoylated proteins, key components in intracellular signal transduction systems enabling rapid and flexible cell responses.

Hayashi N, Titani K - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Bottom Line: Thus, it has been shown that myristoylated proteins in cells regulate the signal transduction between membranes and cytoplasmic fractions.Interestingly, a large portion of the myristoylated proteins thought to take part in signal transduction between membranes and cytoplasmic fractions are included in the predicted myristoylated proteins.On the basis of our recent results, this review will highlight the multifunctional aspects of protein N-myristoylation in brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama-shi, Kanagawa Pref., 226-8501, Japan. nhayashi@bio.titech.ac.jp

ABSTRACT
N-myristoylation, one of the co- or post-translational modifications of proteins, has so far been regarded as necessary for anchoring of proteins to membranes. Recently, we have revealed that N(alpha)-myristoylation of several brain proteins unambiguously regulates certain protein-protein interactions that may affect signaling pathways in brain. Comparison of the amino acid sequences of myristoylated proteins including those in other organs suggests that this regulation is involved in signaling pathways not only in brain but also in other organs. Thus, it has been shown that myristoylated proteins in cells regulate the signal transduction between membranes and cytoplasmic fractions. An algorithm we have developed to identify myristoylated proteins in cells predicts the presence of hundreds of myristoylated proteins. Interestingly, a large portion of the myristoylated proteins thought to take part in signal transduction between membranes and cytoplasmic fractions are included in the predicted myristoylated proteins. If the proteins functionally regulated by myristoylation, a posttranslational protein modification, were understood as cross-talk points within the intracellular signal transduction system, known signaling pathways could thus be linked to each other, and a novel map of this intracellular network could be constructed. On the basis of our recent results, this review will highlight the multifunctional aspects of protein N-myristoylation in brain.

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Chemical structure of the myristoyl moiety. A myristoyl group binds to an N-terminal glycine residue covalently through an amide linkage.
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fig01: Chemical structure of the myristoyl moiety. A myristoyl group binds to an N-terminal glycine residue covalently through an amide linkage.

Mentions: Protein N-myristoylation was first identified in the catalytic subunit of cAMP-dependent protein kinase from bovine cardiac muscle using modern mass spectrometric techniques by K. Titani and his coworkers in 1982.1) After that, calcineurin,2) MMLV p15gag,3) NDAH cytochrome b5 reductase,4) pp 60src 5–8 were found to be myristoylated using similar techniques in succession. The N-termini of proteins are modified with myristate, a 14-carbon saturated fatty acid (Fig. 1), and the enzymology of myristoylation reaction has been well characterized.9) NMT, which exists in all eukaryotes, catalyzes the reaction. In the case of human, two enzymes are known to catalyze the reaction. The substrates are co-translationally myristoylated (Table 1). The myristoylated site is limited to N-terminal glycine, and the linkage is formed by an amide bond. Experiments using substrate peptides have revealed that the enzyme recognizes approximately only ten residues from the N-termini of substrates, and there is no consensus sequence for myristoylation besides glycine at the second position and serine at the sixth position, i.e., MGXXXSXX in the precursor proteins. For myristoylation by NMT, the removal of initiation methionine residue by methionyl aminopeptidase is needed, since exposed glycine residue at N-termini is required. The detection of myristoylation has been difficult because of low chemical reactivities of the myristoyl group, but recent advances in mass spectrometry have made the detection relatively easy. Besides myristoylation, another lipid N-modification was also identified.10) In this article, recent studies on myristoylated proteins including post-genome research studies are described.


N-myristoylated proteins, key components in intracellular signal transduction systems enabling rapid and flexible cell responses.

Hayashi N, Titani K - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2010)

Chemical structure of the myristoyl moiety. A myristoyl group binds to an N-terminal glycine residue covalently through an amide linkage.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3108300&req=5

fig01: Chemical structure of the myristoyl moiety. A myristoyl group binds to an N-terminal glycine residue covalently through an amide linkage.
Mentions: Protein N-myristoylation was first identified in the catalytic subunit of cAMP-dependent protein kinase from bovine cardiac muscle using modern mass spectrometric techniques by K. Titani and his coworkers in 1982.1) After that, calcineurin,2) MMLV p15gag,3) NDAH cytochrome b5 reductase,4) pp 60src 5–8 were found to be myristoylated using similar techniques in succession. The N-termini of proteins are modified with myristate, a 14-carbon saturated fatty acid (Fig. 1), and the enzymology of myristoylation reaction has been well characterized.9) NMT, which exists in all eukaryotes, catalyzes the reaction. In the case of human, two enzymes are known to catalyze the reaction. The substrates are co-translationally myristoylated (Table 1). The myristoylated site is limited to N-terminal glycine, and the linkage is formed by an amide bond. Experiments using substrate peptides have revealed that the enzyme recognizes approximately only ten residues from the N-termini of substrates, and there is no consensus sequence for myristoylation besides glycine at the second position and serine at the sixth position, i.e., MGXXXSXX in the precursor proteins. For myristoylation by NMT, the removal of initiation methionine residue by methionyl aminopeptidase is needed, since exposed glycine residue at N-termini is required. The detection of myristoylation has been difficult because of low chemical reactivities of the myristoyl group, but recent advances in mass spectrometry have made the detection relatively easy. Besides myristoylation, another lipid N-modification was also identified.10) In this article, recent studies on myristoylated proteins including post-genome research studies are described.

Bottom Line: Thus, it has been shown that myristoylated proteins in cells regulate the signal transduction between membranes and cytoplasmic fractions.Interestingly, a large portion of the myristoylated proteins thought to take part in signal transduction between membranes and cytoplasmic fractions are included in the predicted myristoylated proteins.On the basis of our recent results, this review will highlight the multifunctional aspects of protein N-myristoylation in brain.

View Article: PubMed Central - PubMed

Affiliation: Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama-shi, Kanagawa Pref., 226-8501, Japan. nhayashi@bio.titech.ac.jp

ABSTRACT
N-myristoylation, one of the co- or post-translational modifications of proteins, has so far been regarded as necessary for anchoring of proteins to membranes. Recently, we have revealed that N(alpha)-myristoylation of several brain proteins unambiguously regulates certain protein-protein interactions that may affect signaling pathways in brain. Comparison of the amino acid sequences of myristoylated proteins including those in other organs suggests that this regulation is involved in signaling pathways not only in brain but also in other organs. Thus, it has been shown that myristoylated proteins in cells regulate the signal transduction between membranes and cytoplasmic fractions. An algorithm we have developed to identify myristoylated proteins in cells predicts the presence of hundreds of myristoylated proteins. Interestingly, a large portion of the myristoylated proteins thought to take part in signal transduction between membranes and cytoplasmic fractions are included in the predicted myristoylated proteins. If the proteins functionally regulated by myristoylation, a posttranslational protein modification, were understood as cross-talk points within the intracellular signal transduction system, known signaling pathways could thus be linked to each other, and a novel map of this intracellular network could be constructed. On the basis of our recent results, this review will highlight the multifunctional aspects of protein N-myristoylation in brain.

Show MeSH
Related in: MedlinePlus