Myristoyl switch

Ames, J.B., Ishima, R., Tanaka, T, Gordon, J.I., Stryer, L. and Ikura, M. Molecular mechanics of calcium-myristoyl switches (1997) Nature 389, 198-202... 

Goldberg J Structural basis for activation of ARE GTPase mechanisms of guanine nucleotide exchange and GTP-myristoyl switching (1998) Cell 95, 237-248... 

Recoverin is a Ca receptor with four EF structures and two Ca binding sites it can exist in the cytosol or associated with the membrane and has an N-terminal myristoyl residue as a lipid anchor. The distribution between free and membrane-associated forms is regulated by Ca. Binding of Ca to recoverin leads to its translocation from the cytosol to the membrane of the rod cells. Structural determination of recoverin in the Ca bound and Ca free forms (Ames et al., 1997) indicates that membrane association of recoverin is regulated by a Ca -myristoyl switch. The myristoyl residue can adopt two alternative positions in recoverin. In the absence of Ca, recoverin exists in a conformation in which the myristoyl residue is hidden in the iimer of the protein and is not available for membrane association. On Ca binding, a conformation change of recoverin takes place the myristoyl residue moves to the outside and can now associate with the membrane. 

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. 

J.I., Stryer, L. and Ikura, M. (1997) Molecular mechanics of calcium-myristoyl switches. 

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.

Lastly, both myristoylation and palmitoylation may occur dynamically, and their reactions may be used as regulatory switches for the signal transduction systems (Milligan et al., 1995 McLaughlin and Aderem, 1995). 

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. 3.12. Model of the switch function of the myristoyl anchor in signal proteins.

Myristoylation is generally considered a constitutive process and a permanent modification. As shown above the myristoic anchor may function as a switch during regulated membrane anchoring. Examples for myristoylated proteins are the cytoplasmic protein tyrosine kinases (family of the Src-kinases, chapter 8), as well as the a-subunit of the heterotrim eric G-proteins (chapter 5). 

Hantschel O, Nagar B, Guettler S et al. A myristoyl/phosphotyrosine switch regulates c-Abl. Cell 2003 112 845-857. 

Randazzo PA, Terui T, Sturch S, et al. (1995) The myristoylated amino terminus of ADP-ribosylation factor 1 is a phospholipid- and GTP-sensitive switch. In J. Biol. Chem. 270 14809-14815. 

Fig. 3.16 Model of the switch function of the myristoyl anchor in signal proteins The myristoyl anchorof a signal protein can exist in a state accessible for membrane insertion or in a state buried in the interior of the protein. The transition between the two states may be controlled by specific cellular signals (e.g. Ca2+, CDP/CTP exchange). In the membrane-associated form, interactions with membrane-bound effector proteins become possible and the signal can be transduced further.

The membrane association of fatty acylated and prenylated proteins is reversible and can be regulated in a number of ways, using switches that obscure the primary lipid modification or affect the strength of the second signal (Fig. 3). For example, phosphorylation of the polybasic domain of A-myristoylated MARCKS reduces the strength of the second signal and causes MARCKS to dissociate from membranes (S. McLaughlin, 1995). 

Hanakam F, Getisch G, Lotz S, Alt T, SeeUg A (1996) Binding of hisactopMlin 1 and 11 to lipid membranes is controlled by a pH-dependent myristoyl-histidine switch. Biochemistry 35 11036-11044... 

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