A myristoyl switch regulates membrane binding of HIV-1 Gag

Resh, Marilyn D.

doi:10.1073/pnas.0308043101

Cited by 84 publications

(73 citation statements)

References 26 publications

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“…Here, we show that Gag multimerization is indeed required for efficient membrane binding in cells, because it overcomes an activity in the globular head of HIV-1 matrix (MA) that inhibits membrane association. These effects confer concentration dependence on the HIV-1 Gag-membrane interaction and are consistent with the notion that multimerization triggers the "myristoyl switch" (18,22,25), thereby imparting a high degree of cooperativity on HIV-1 Gag trafficking to membranes.…”

supporting

confidence: 83%

Human Immunodeficiency Virus Type 1 Matrix Inhibits and Confers Cooperativity on Gag Precursor-Membrane Interactions

Pérez-Caballero

Hatziioannou

Martín-Serrano

et al. 2004

J Virol

103

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Human immunodeficiency virus type 1 (HIV-1) Gag multimerization and membrane binding are required for particle formation. However, it is unclear what constitutes a minimal plasma membrane-specific targeting signal and what role the matrix (MA) globular head and other Gag domains play in membrane targeting. Here, we use membrane flotation and microscopic analysis of Gag deletion mutants to demonstrate that the HIV-1 MA globular head inhibits a plasma membrane-specific targeting signal contained within the six amino-terminal MA residues. MAmediated inhibition is relieved by concentration-dependent Gag multimerization and imparts a high degree of cooperativity on Gag-membrane association. This cooperativity may confer temporal and spatial regulation on HIV-1 assembly.

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supporting

confidence: 83%

Human Immunodeficiency Virus Type 1 Matrix Inhibits and Confers Cooperativity on Gag Precursor-Membrane Interactions

Pérez-Caballero

Hatziioannou

Martín-Serrano

et al. 2004

J Virol

103

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“…Based on these observations we speculate that the partitioning of Src-Vac8 into the aqueous phase could reflect the ability of the Vac8 moiety to accommodate the hydrophobic myristoyl tail within the protein. Such a switch-like mechanism has been discussed for other myristoylated proteins like HIV-Gag (Resh, 2004).…”

Section: Discussionmentioning

confidence: 99%

Palmitoylation determines the function of Vac8 at the yeast vacuole

Subramanian

Dietrich

Hou

et al. 2006

Journal of Cell Science

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Palmitoylation stably anchors specific proteins to membranes, but may also have a direct effect on the function of a protein. The yeast protein Vac8 is required for efficient vacuole fusion, inheritance and cytosol-to-vacuole trafficking. It is anchored to vacuoles by an N-terminal myristoylation site and three palmitoylation sites, also known as the SH4 domain. Here, we address the role of Vac8 palmitoylation and show that the position and number of substrate cysteines within the SH4 domain determine the vacuole localization of Vac8: stable vacuole binding of Vac8 requires two cysteines within the N-terminus, regardless of the combination. Importantly, our data suggest that palmitoylation adds functionality to Vac8 beyond simple localization. A mutant Vac8 protein, in which the palmitoylation sites were replaced by a stretch of basic residues, still localizes to vacuole membranes and functions in cytosol-to-vacuole transport, but can only complement the function of Vac8 in morphology and inheritance if it also contains a single cysteine within the SH4 domain. Our data suggest that palmitoylation is not a mere hydrophobic anchor required solely for localization, but influences the protein function(s).

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“…In the case of HIV infections, viral proteins Gag and Nef require myristoylation by the host cell NMT to carry out their function properly. Gag is the precursor polyprotein for structural components of the viral capsid and requires myristoylation for intracellular localization and its targeting to the lipid rafts in the plasma membrane during virus assembly (Zhou et al, 1994;Resh, 2004;Wright et al, 2009). Nef on the other hand comprises many virulence factors to modify the cellular environment of infected cells to facilitate viral replication and evade detection by cells of the immune system (Collins et al, 1998).…”

Section: Diseasementioning

confidence: 99%