![]() In addition, heteroatom-substituted myristic acid analogs such as 12-methoxydodecanoic acid can be used by NMT as alternative substrates for covalent attachment to proteins. For example, NMT inhibitors have been shown to prevent both membrane binding of Gag as well as virus assembly ( 5). Several studies have considered NMT as a potential drug target for the inhibition of retroviral assembly and as a general antimicrobial agent ( 4). N-myristoylation of proteins is catalyzed by the enzyme N-myristoyl transferase (NMT), which uses myristoyl-CoA as a substrate ( 4). Cotranslational modification of Gag with the saturated fatty acid myristic acid (tetradecanoic acid, abbreviated here as 14:0) to the N-terminal glycine is required for the binding of Gag to cellular membranes as well as the subsequent assembly and budding of virions/VLPs ( 3). These particles resemble immature virions and can be isolated from the cell-culture medium. VLPs consist of a multimerized array of 1,000–1,500 Gag molecules surrounded by a lipid envelope obtained from the host cell plasma membrane ( 2). ![]() These studies suggest a strategy to attack HIV assembly by selectively altering the patterns of fatty acid modification.Įxpression of the HIV-1 Gag protein is necessary and sufficient for the production of virus-like particles (VLPs ref. Treatment with 14:1 n-9 and 14:2 n-6 fatty acids did not alter intracellular protein trafficking, nor did it reduce cell viability. These effects most likely reflect covalent modification of Gag with unsaturated fatty acids. Furthermore, treatment of cells with 14-carbon unsaturated fatty acids inhibited Gag-driven particle assembly. Here we demonstrate that treatment of cells with 14:1 n-9 and 14:2 n-6 fatty acids reduced the affinity of Gag for rafts but not membranes in general. We recently showed that exogenous treatment of cells with unsaturated 14-carbon fatty acids, 5- cis-tetradecenoic acid (14:1 n-9) and 5- cis,8- cis-tetradecadienoic acid (14:2 n-6), reduces the affinity of some myristoylated proteins for plasma membrane rafts, membrane subdomains that have been shown to be required for efficient assembly of HIV. ![]() Modification of HIV-1 Gag with myristic acid, a saturated 14-carbon fatty acid (14:0), is essential for HIV-1 assembly. ![]()
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