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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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Related in: MedlinePlus

A comparison between the canonical CaM-binding peptide, TFP, and the myristoylated mC/N9. A space-filling model of the M13 peptide derived from skeletal muscle MLCK in a helical conformation (top); the hydrophobic amino acid residues that play important roles in the CaM interaction are shown in red, and the positively charged amino acid residues are shown in blue. TFP (middle); the hydrophobic aromatic group is shown in red, and the positively charged group is shown in blue. The myristoylated N-terminal peptide of CAP-23/NAP-22 (myr-GGKLSKKKK) in an elongated structure (bottom); the myristoyl moiety and Leu4 are shown in red; the positively charged amino acid residues are shown in blue, and one phosphorylatable amino acid residue, Ser5, is shown in yellow. All of these molecules include the basic amphiphilic natures (basic group—blue, hydrophobic group—red) in them.
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fig08: A comparison between the canonical CaM-binding peptide, TFP, and the myristoylated mC/N9. A space-filling model of the M13 peptide derived from skeletal muscle MLCK in a helical conformation (top); the hydrophobic amino acid residues that play important roles in the CaM interaction are shown in red, and the positively charged amino acid residues are shown in blue. TFP (middle); the hydrophobic aromatic group is shown in red, and the positively charged group is shown in blue. The myristoylated N-terminal peptide of CAP-23/NAP-22 (myr-GGKLSKKKK) in an elongated structure (bottom); the myristoyl moiety and Leu4 are shown in red; the positively charged amino acid residues are shown in blue, and one phosphorylatable amino acid residue, Ser5, is shown in yellow. All of these molecules include the basic amphiphilic natures (basic group—blue, hydrophobic group—red) in them.

Mentions: In the case of M13 (the CaM-binding domain of MLCK), the amphiphilic nature of the peptide required for its binding to CaM was induced by the α-helical conformation. The CaM-binding domain of CAP-23/NAP-22 adopted a non-helical conformation in the Ca2+/CaM-complex.14) The N-terminal domain of CAP-23/NAP-22 contained one hydrophobic residue (Leu4) in addition to five basic residues (Lys3, Lys6, Lys7, Lys8 and Lys9). In this domain, one hydrophobic acyl group (N-terminal myristoyl moiety) was followed by one basic residue (Lys3) and then one hydrophobic residue (Leu4). This result resembled the canonical CaM-binding motif, in which positively charged hydrophilic and hydrophobic residues alternated.37,38) If the acyl group had been substituted for a large hydrophobic residue, such as Trp or Leu found in the canonical CaM-binding motif, the overall structural characteristics would have appeared to be very similar to each other. The distance between the myristoyl moiety and Leu4 was comparable to that between the two critical hydrophobic residues found in M13 (Fig. 8; shown in red). TFP and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) are small compounds known to bind to CaM.39) Although the chemical structure of TFP/W-7 clearly differed from that of mC/N9 or M13, it also contained hydrophobic groups (Fig. 8; shown in red) as well as positively charged groups (Fig. 8; shown in blue), and these groups were the cause of the amphiphilic nature of the molecule. All these observations together emphasized the importance of the amphiphilic nature required for the binding of CaM-binding molecules, not only proteins but also bioactive small molecules, to Ca2+/CaM.


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)

A comparison between the canonical CaM-binding peptide, TFP, and the myristoylated mC/N9. A space-filling model of the M13 peptide derived from skeletal muscle MLCK in a helical conformation (top); the hydrophobic amino acid residues that play important roles in the CaM interaction are shown in red, and the positively charged amino acid residues are shown in blue. TFP (middle); the hydrophobic aromatic group is shown in red, and the positively charged group is shown in blue. The myristoylated N-terminal peptide of CAP-23/NAP-22 (myr-GGKLSKKKK) in an elongated structure (bottom); the myristoyl moiety and Leu4 are shown in red; the positively charged amino acid residues are shown in blue, and one phosphorylatable amino acid residue, Ser5, is shown in yellow. All of these molecules include the basic amphiphilic natures (basic group—blue, hydrophobic group—red) in them.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig08: A comparison between the canonical CaM-binding peptide, TFP, and the myristoylated mC/N9. A space-filling model of the M13 peptide derived from skeletal muscle MLCK in a helical conformation (top); the hydrophobic amino acid residues that play important roles in the CaM interaction are shown in red, and the positively charged amino acid residues are shown in blue. TFP (middle); the hydrophobic aromatic group is shown in red, and the positively charged group is shown in blue. The myristoylated N-terminal peptide of CAP-23/NAP-22 (myr-GGKLSKKKK) in an elongated structure (bottom); the myristoyl moiety and Leu4 are shown in red; the positively charged amino acid residues are shown in blue, and one phosphorylatable amino acid residue, Ser5, is shown in yellow. All of these molecules include the basic amphiphilic natures (basic group—blue, hydrophobic group—red) in them.
Mentions: In the case of M13 (the CaM-binding domain of MLCK), the amphiphilic nature of the peptide required for its binding to CaM was induced by the α-helical conformation. The CaM-binding domain of CAP-23/NAP-22 adopted a non-helical conformation in the Ca2+/CaM-complex.14) The N-terminal domain of CAP-23/NAP-22 contained one hydrophobic residue (Leu4) in addition to five basic residues (Lys3, Lys6, Lys7, Lys8 and Lys9). In this domain, one hydrophobic acyl group (N-terminal myristoyl moiety) was followed by one basic residue (Lys3) and then one hydrophobic residue (Leu4). This result resembled the canonical CaM-binding motif, in which positively charged hydrophilic and hydrophobic residues alternated.37,38) If the acyl group had been substituted for a large hydrophobic residue, such as Trp or Leu found in the canonical CaM-binding motif, the overall structural characteristics would have appeared to be very similar to each other. The distance between the myristoyl moiety and Leu4 was comparable to that between the two critical hydrophobic residues found in M13 (Fig. 8; shown in red). TFP and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) are small compounds known to bind to CaM.39) Although the chemical structure of TFP/W-7 clearly differed from that of mC/N9 or M13, it also contained hydrophobic groups (Fig. 8; shown in red) as well as positively charged groups (Fig. 8; shown in blue), and these groups were the cause of the amphiphilic nature of the molecule. All these observations together emphasized the importance of the amphiphilic nature required for the binding of CaM-binding molecules, not only proteins but also bioactive small molecules, to Ca2+/CaM.

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