Myristoyl-electrostatic switches

McLaughlin, S., and Aderem, A. (1995). The myristoyl-electrostatic switch a modulator of reversible protein-membrane interactions. Trends Biochem. Sci. 20, 272—276. 

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 ... 

Fig. 3. Reversible membrane association of lipidated proteins (redrawn firom Ref. [11]). (a) Binding of a ligand (shaded circle) to an iV-myristoylated protein triggers a myristoyl switch, (b) Binding of a ligand (shaded oval) to the polybasic motif of a singly lipidated protein reduces the second signal allowing the protein to desorb from membranes, (c) Phosphorylation within the polybasic motif lowers its affinity for anionic phospholipids (electrostatic switch), (d) A prenyl group is sequestered by a binding partner, (e) Lipidated secreted proteins (the star represents a lipid modification cholesterol and/or fatty acid) spread ftom their source by binding to lipoprotein carriers.

Another type of myristoyl switch has been reported for the MRACKS proteins which are substrates of protein kinase C (see Section 7.4). The membrane binding of the MARCKS proteins is mediated by myristate plus basic motif. Protein kinase C phosphorylation within the basic motif introduces negative charges into the positively charged region. This reduces the electrostatic interactions with the acidic phospholipids and results in displacement of the MARCKS proteins from the membrane and into the cytosol. 

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