N-Myristoylation

Fyn is a nonreceptor tyrosine kinase related to Src that is frequently found in cell junctions. Die protein is N-myristoylated and palmitoylated and thereby becomes associated with caveolae-like membrane microdomains. Fyn can interact with a variety of other signaling molecules and control a diversity of biological processes such as T cell receptor signaling, regulation of brain function, and adhesion mediated signaling. 

Farazi TA, Waksman G, Gordon JT (2001) The biology and enzymology of protein N-myristoylation. J Biol Chem 276 39501-39504... 

Deacylation or hydrolysis of chiral carbamates, carbonates and alkanoates Micelles and comicelles of N-hexadecyl-N-methylephedrinium bromide or N -myristoyl-histidine with CTABr. Rate effects and enantioselectivities examined Fomasier and Tonellato, 1984... 

Mcllhnney, R. (1998). Membrane targeting via protein N-myristoylation. Methods Mol. Biol. 88, 211-225. 

Hasegawa, K., Shindoh, H., Shiratori, Y., Ohtsuka, T., Aoki, Y., Ichihara, S., Horii, L, and Shimma, N. Cassette dosing approach and quantitative structure-pharmacokinetic relationship study of antifungal N-myristoyl-transferaseinhibitors./. Chem. Inf. Comput. Sci. 2002, 42, 968—975. 

N-Myristoylation is achieved by the covalent attachment of the 14-carbon saturated myristic acid (C14 0) to the N-terminal glycine residue of various proteins with formation of an irreversible amide bond (Table l). 10 This process is cotranslational and is catalyzed by a monomeric enzyme called jV-myri s toy 11ransferase. 24 Several proteins of diverse families, including tyrosine kinases of the Src family, the alanine-rich C kinase substrate (MARKS), the HIV Nef phosphoprotein, and the a-subunit of heterotrimeric G protein, carry a myr-istoylated N-terminal glycine residue which in some cases is in close proximity to a site that can be S-acylated with a fatty acid. Functional studies of these proteins have shown an important structural role for the myristoyl chain not only in terms of enhanced membrane affinity of the proteins, but also of stabilization of their three-dimensional structure in the cytosolic form. Once exposed, the myristoyl chain promotes membrane association of the protein. 5 The myristoyl moiety however, is not sufficiently hydrophobic to anchor the protein to the membrane permanently, 25,26 and in vivo this interaction is further modulated by a variety of switches that operate through covalent or noncovalent modifications of the protein. 4,5,27 In MARKS, for example, multiple phosphorylation of a positively charged domain moves the protein back to the cytosolic compartment due to the mutated electrostatic properties of the protein, a so-called myristoyl-electrostatic switch. 28 ... 

In particular cases where small amounts of myristoylated peptides are required, enzymatic N-myristoylation of unprotected and purified peptides can be achieved using the yeast TV-myristoyltransferase. This procedure has been applied for N-myristoylation of the N-terminal deca-, dodeca-, and tetradecamer fragment of pp60vsrc, the transforming protein of Rous sarcoma virus. 31 This method is particularly useful when [3H]-labeled myristoylated compounds are required. 

As discussed for N-myristoylation and S-prenylation, even S-acylation of proteins with a fatty acid which in the vast majority of cases is the C16 0 palmitic acid, plays a fundamental role in the cellular signal-transduction process (Table l). 2-5 14 While N-myristoylation and S-prenylation are permanent protein modifications due to the amide- and sulfide-type linkage, the thioester bond between palmitic acid and the peptide chain is rather labile and palmi-toylation is referred to as a dynamic modification. 64 This reversibility plays a crucial role in the modulation of protein functions since the presence or absence of a palmitoyl chain can determine the membrane localization of the protein and can also be used to regulate the interactions of these proteins with other proteins. Furthermore, a unique consensus sequence for protein palmitoylation has not been found, in contrast to the strict consensus sequences required for N-myristoylation and S-prenylation. Palmitoylation can occur at N- or C-terminal parts of the polypeptide chain depending on the protein family and often coexists with other types of lipidation (see Section 6.4.1.4). Given the diversity of protein sequences... 

To mimic nature in its irreversible monolipidation of proteins by N-myristoylation and S-prenylation, peptides are N-acylated with fatty acids or N-alkylated with linear or branched, saturated or unsaturated aliphatic chains as well as by incorporation of newly synthesized lipo-amino acids. 

Sakurai, N., Moriya, K., Suzuki, T., Sofiiku, K, Motiki, H., Nishimura, O., and Utsmni, T. (2007) Detection of co- and post-translational protein N-myristoylation by metabolic labeling in an insect cell-free protein synthesis system. Anal. Biochem. 362, 236-244. 

N-myristoyl o (l heteratrimeric G-proteins (a-sjbunit), see chapter S cytoplasmic tyrosine kinases, see chapter 8 N-terminus... 

Acylation and prenylation. The amino terminus (usually glycine) of the a subunit of any G protein is nearly always converted to an N-myristoyl group.220-223 This modification occurs in a cotranslational process after removal of the initiating methionine (Chapter 29) and can be described as an acyl transfer from coenzyme A.224 The C termini of the y subunits of heterotrimeric G proteins, and also of the monomeric proteins of the Ras family, also undergo processing. For example, the C-terminal end of an intact Ras protein contains 18 residues which probably assume a largely a-helical conformation. A cysteine side chain near the terminus and having the sequence CAAX is... 

King, M. 1., and Sharma, R. K. 1992. Demonstration of multiple forms of bovine brain myristoyl CoA protein N-myristoyl transferase. Mol. Cell. Biochem. 113 77-81. 

Maurer-Stroh S, Eisenhaber B, Eisenhaber F. 2002. N-terminal N-myristoylation of proteins Prediction of substrate... 

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