Myristoyl

Four different types of lipid-anchoring motifs have been found to date. These are amide-linked myristoyl anchors, thioester-linked fatty acyl anchors, thioether-linked prenyl anchors, and amide-linked glycosyl phosphatidylinosi-tol anchors. Each of these anchoring motifs is used by a variety of membrane proteins, but each nonetheless exhibits a characteristic pattern of structural requirements. 

Myristic acid may be linked via an amide bond to the a-amino group of the N-terminal glycine residue of selected proteins (Figure 9.18). The reaction is referred to as A -myristoylation and is catalyzed by myristoyl—CoAtprolein N-myris-toyltransferase, known simply as NMT. A -Myristoyl-anchored proteins include the catalytic subunit of cAMP-dependent protein kinase, the ppSff tyrosine kinase, the phosphatase known as calcineurin B, the a-subunit of G proteins (involved in GTP-dependent transmembrane signaling events), and the gag proteins of certain retroviruses, including the FHV-l virus that causes AIDS. 

A variety of cellular and viral proteins contain fatty acids covalently bound via ester linkages to the side chains of cysteine and sometimes to serine or threonine residues within a polypeptide chain (Figure 9.18). This type of fatty acyl chain linkage has a broader fatty acid specificity than A myristoylation. Myristate, palmitate, stearate, and oleate can all be esterified in this way, with the Cjg and Cjg chain lengths being most commonly found. Proteins anchored to membranes via fatty acyl thioesters include G-protein-coupled receptors, the surface glycoproteins of several viruses, and the transferrin receptor protein. 

Look al the catabolism of my fistic acid shown in Figure 29.4 to see the overall results of the /3-oxidation pathway. The first passage converts the 14-carbon myristoyl CoA into the 12-carbon lauroyl CoA plus acetyl CoA, the second passage converts lauroyl CoA into the 10-carbon caproyl CoA plus acetyl CoA, the third passage converts caproyl CoA into the 8-carbon capryloyl CoA, and so on. Note that the final passage produces two molecules of acetyl CoA because the precursor has four carbons. 

Ferri, S. R., and Meighen, E. A. (1991). A Lux-specific myristoyl transferase in luminescent bacteria related to eukaryotic serine esterases. J. Biol. Chem. 266 12852-12857. 

This family contains more than 40 members subdivided into five subfamilies [4]. The NCS have been involved in phototransduction and regulation of neurotransmitter release. The NCS have two pairs of EF-hands and, unlike CaM and SI00 proteins, possess a consensus myristoylation sequence at the N-terminal responsible for the targeting of the NCS to the membrane. 

Members of the first group of NCS are recoverin and visinin. Recoverin is a 23 kDa myristoylated protein found under normal conditions only in photoreceptor cells (rods and cones). The main function of recoverin is to bind to and inhibit rhodopsin kinase, thereby prolonging the light response. 

Calcineurin homologous protein (CHP) is ubiquitously expressed and has four EF-hand domains and one putative site of 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. 

Lipidation -acylation TV -myristoylation Myristoy-lation S-prenylation Prenylation Palmitoylation Isoprenylation GPI anchors Glypiation... 

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

Myristoylation is the post-translational addition of the 14-carbon fatty acid myristate to the N-terminal glycine of proteins via an amide link. Myristoylation of proteins helps to anchor them to membranes. 

TRAM was the fourth adapter discovered and has only been seen to have a role in TLR-4 signalling. It contains a TIR domain and a myristoylation site. When TRAM is myristoylated it becomes bound to the plasma membrane and can bind to TLR-4 through its TER. domain. TRAM then allows TRIF to bind it and activate the pathways associated with TRIF as outlined above for TLR-3. 

TRAM is subject to control through phosphorylation by protein kinase C-e. It is phosphorylated on serine 16 which is located close to the myristoylation site which is TRAM cannot signal without this phosphorylation or if the myristoylation site has been mutated. 

Figure 2. NMR spectra of PPO acylated with propionyl chloride (Sample No. 8, Table III) (IV), PPO acylated with myristoyl chloride (Sample No. 11, Table III) (V), and PPO acylated with -toluoyl chloride (Sample No. 14, Table III) (VI). (Reproduced with permission from ref. 17. Copyright 1987 Wiley.)...

The increase in the length of the side chain results normally in an internal plasticization effect caused by a lower polarity of the main chain and an increase in the configurational entropy. Both effects result in a lower activation energy of segmental motion and consequently a lower glass transition temperature. The modification of PPO with myristoyl chloride offers the best example. No side chain crystallization was detected by DSC for these polymers. 

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