Coarse-Grained Simulations of the HIV-1 Matrix Protein Anchoring: Revisiting Its Assembly on Membrane Domains

Charlier, Landry; Louet, Maxime; Chaloin, Laurent; Fuchs, Patrick; Martinez, Jean; Muriaux, Delphine; Favard, Cyril; Floquet, Nicolas

doi:10.1016/j.bpj.2013.12.019

Cited by 76 publications

(129 citation statements)

References 44 publications

(65 reference statements)

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“…We note that the deep penetration of MA 31 myr from our NR experiments do not agree with the much shallower penetration obtained from a coarse grained simulation of MA [58] that has not been validated against experimental structure involving a lipid bilayer. It is, of course, possible that the first 31 amino acids in the full MA reside less deeply in the membrane than our truncated peptides; the water soluble amino acids not included in our reductionist study might pull the binding sites towards the water.…”

Section: Location Of the Peptides In The Membrane Mimicscontrasting

confidence: 94%

HIV-1 Matrix-31 Membrane Binding Peptide Interacts Differently with Membranes Containing PS vs. PI(4,5)P 2

O'neil

Andenoro

Pagano

et al. 2017

Biophysical Journal

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Efficient assembly of HIV-1 at the plasma membrane (PM) of the T-cell specifically requires PI(4,5)P 2 . It was previously shown that a highly basic region (HBR) of the matrix protein (MA) on the Gag precursor polyprotein Pr55 Gag is required for membrane association. MA is N-terminally myristoylated, which enhances its affinity to membranes. In this work we used X-ray scattering and neutron reflectivity to determine how the physical properties and structure of lipid bilayers respond to the addition of binding domain peptides, either in the myristoylated form (MA 31 myr) or without the myristoyl group (MA 31 ). Neutron reflectivity measurements showed the peptides predominantly located in the hydrocarbon interior. Diffuse X-ray scattering showed differences in membrane properties upon addition of peptides and the direction of the changes depended on lipid composition. The PI(4,5)P 2 -containing bilayers softened, thinned and became less ordered as peptide concentration increased. In contrast, POPS-containing bilayers with equivalent net charge first stiffened, thickened and became more ordered with increasing peptide concentration. As softening the host cell's PM upon contact with the protein lowers the free energy for membrane restructuring, thereby potentially facilitating budding of viral particles, our results suggest that the role of PI(4,5)P 2 in viral assembly goes beyond specific stereochemical membrane binding. These studies reinforce the importance of lipids in virology.

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Section: Location Of the Peptides In The Membrane Mimicscontrasting

confidence: 94%

HIV-1 Matrix-31 Membrane Binding Peptide Interacts Differently with Membranes Containing PS vs. PI(4,5)P 2

O'neil

Andenoro

Pagano

et al. 2017

Biophysical Journal

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“…Because PC headgroups are bulky and therefore are likely to reduce MA binding to PI(4,5)P 2 , it is conceivable that cholesterol facilitates MA access to PI(4,5)P 2 by spacing out the surrounding DOPC headgroups. Moreover, recent MD simulations suggested that MA may induce lateral segregation of PI(4,5)P 2 into domains which may by itself promote efficient MA binding, for example through locally enhanced electrostatic interactions (78). There is also experimental evidence that cholesterol helps stabilize PI(4,5)P 2 in lipid clusters (79), which rationalizes that cholesterol and PI(4,5)P 2 synergistically attract MA to the membrane, as shown in Fig.…”

Section: Discussionmentioning

confidence: 81%

Membrane Binding of HIV-1 Matrix Protein: Dependence on Bilayer Composition and Protein Lipidation

Barros

Heinrich

Datta

et al. 2016

J Virol

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By assembling in a protein lattice on the host's plasma membrane, the retroviral Gag polyprotein triggers formation of the viral protein/membrane shell. The MA domain of Gag employs multiple signals-electrostatic, hydrophobic, and lipid-specific-to bring the protein to the plasma membrane, thereby complementing protein-protein interactions, located in full-length Gag, in lattice formation. We report the interaction of myristoylated and unmyristoylated HIV-1 Gag MA domains with bilayers composed of purified lipid components to dissect these complex membrane signals and quantify their contributions to the overall interaction. Surface plasmon resonance on well-defined planar membrane models is used to quantify binding affinities and amounts of protein and yields free binding energy contributions, ⌬G, of the various signals. Charge-charge interactions in the absence of the phosphatidylinositide PI(4,5)P 2 attract the protein to acidic membrane surfaces, and myristoylation increases the affinity by a factor of 10; thus, our data do not provide evidence for a PI(4,5)P 2 trigger of myristate exposure. Lipid-specific interactions with PI(4,5)P 2 , the major signal lipid in the inner plasma membrane, increase membrane attraction at a level similar to that of protein lipidation. While cholesterol does not directly engage in interactions, it augments protein affinity strongly by facilitating efficient myristate insertion and PI(4,5)P 2 binding. We thus observe that the isolated MA protein, in the absence of protein-protein interaction conferred by the full-length Gag, binds the membrane with submicromolar affinities. IMPORTANCELike other retroviral species, the Gag polyprotein of HIV-1 contains three major domains: the N-terminal, myristoylated MA domain that targets the protein to the plasma membrane of the host; a central capsid-forming domain; and the C-terminal, genome-binding nucleocapsid domain. These domains act in concert to condense Gag into a membrane-bounded protein lattice that recruits genomic RNA into the virus and forms the shell of a budding immature viral capsid. In binding studies of HIV-1 Gag MA to model membranes with well-controlled lipid composition, we dissect the multiple interactions of the MA domain with its target membrane. This results in a detailed understanding of the thermodynamic aspects that determine membrane association, preferential lipid recruitment to the viral shell, and those aspects of Gag assembly into the membrane-bound protein lattice that are determined by MA. T he polyprotein Gag is an essential component for the reproduction of retroviruses, such as HIV-1, in infected cells. In the production of new viruses, many copies of Gag assemble laterally, either in the cytoplasm or on the plasma membrane (PM) of the host, thus acquiring their lipid envelope as they bud from the cell. Distinct retroviral genera encode Gag proteins which all show a similar domain architecture, with an N-terminal matrix (MA) domain that targets the PM, followed by the capsid (CA) and nucleocapsid ...

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“…Therefore, it is tempting to speculate that interactions of MA HBR with acidic lipids such as PI(4,5)P 2 and PS nucleate the formation of microdomains rich in acidic lipids, which in turn attract membrane proteins that have membrane-proximal basic clusters. Indeed, this possibility is supported by a recent simulation study in which MA is capable of sequestering PI(4,5)P 2 molecules (38). Alternatively, it is plausible that Gag localizes to pre-existing microdomains that are enriched in acidic lipids and uropod-directed transmembrane proteins.…”

Section: Relationships Between Gag Membrane Binding and Microdomain Omentioning

confidence: 78%

“…However, involvement of MA structural changes in the context of full length Gag and in the presence of lipid bilayers remains to be tested. Likewise, the requirement for various triggers remains to be examined in the presence of lipid bilayers, since spontaneous myristoyl exposure has been observed in NMR (37) and in silico (38). …”

Section: Membrane Binding Of Gag Via Bipartite Signals Within Mamentioning

confidence: 99%

Roles played by acidic lipids in HIV-1 Gag membrane binding

Olety¹,

Ono²

2014

Virus Research

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The MA domain mediates plasma membrane (PM) targeting of HIV-1 Gag, leading to particle assembly at the PM. The interaction between MA and acidic phospholipids, in addition to N-terminal myristoyl moiety, promotes Gag binding to lipid membranes. Among acidic phospholipids, PI(4,5)P2, a PM-specific phosphoinositide, is essential for proper HIV-1 Gag localization to the PM and efficient virus particle production. Recent studies further revealed that MA-bound RNA negatively regulates HIV-1 Gag membrane binding and that PI(4,5)P2 is necessary to overcome this RNA-imposed block. In this review, we will summarize the current understanding of Gag-membrane interactions and discuss potential roles played by acidic phospholipids.

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Coarse-Grained Simulations of the HIV-1 Matrix Protein Anchoring: Revisiting Its Assembly on Membrane Domains

Cited by 76 publications

References 44 publications

HIV-1 Matrix-31 Membrane Binding Peptide Interacts Differently with Membranes Containing PS vs. PI(4,5)P 2

HIV-1 Matrix-31 Membrane Binding Peptide Interacts Differently with Membranes Containing PS vs. PI(4,5)P 2

Membrane Binding of HIV-1 Matrix Protein: Dependence on Bilayer Composition and Protein Lipidation

Roles played by acidic lipids in HIV-1 Gag membrane binding

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