Retroviral matrix and lipids, the intimate interaction

Abstract

Retroviruses are enveloped viruses that assemble on the inner leaflet of cellular membranes. Improving biophysical techniques has recently unveiled many molecular aspects of the interaction between the retroviral structural protein Gag and the cellular membrane lipids. This interaction is driven by the N-terminal matrix domain of the protein, which probably undergoes important structural modifications during this process, and could induce membrane lipid distribution changes as well. This review aims at describing the molecular events occurring during MA-membrane interaction, and pointing out their consequences in terms of viral assembly. The striking conservation of the matrix membrane binding mode among retroviruses indicates that this particular step is most probably a relevant target for antiviral research.

Figure 1

A structural overview of retroviral MAs. (A): Structural superimposition of MLV (1MN8), RSV (1A6S) and HIV (1TAM) MA proteins. Superimposition obtained using the combinatorial extension method (CE) and the image was generated with Viewer Pro software (Accelrys), thanks to E. Derivery. (B): Scheme of the [T] to [R] switch. [T] conformation sequesters the myristate of myristylated MAs, and remains monomeric, while [R] conformation associates in trimers and exposes the myristate (when present).

Figure 2

Some lipid components of the internal leaflet of cellular membranes. Main lipid components of the internal leaflet of cellular membranes are represented: phosphatidylcholine (PC), Phosphatidylethanolamine (PE), phosphatidylserine (PS), Phosphatidylinositol phosphates (here, PI(4,5)P₂) and cholesterol. In membrane bilayers, the polar heads (top) face the cytosol, while the hydrophobic fatty acid chains (bottom) face the hydrophobic tails of the other leaflets's lipids.

Figure 3

A model for [T] to [R] equilibrium in different conditions. Some elements are susceptible to influence the MA [T] vs [R] equilibrium, in the context of MA alone (in the mature particle, during the early step of infection, or in vitro), or as a domain of the Gag polyprotein. The "initial" equilibrium (in solution, purified protein, concentration around 1 μM) between the [T] and [R] conformations of HIV (A) and MLV (B) MAs (a) or Gag (b) are depicted, the size of the protein representing the relative amount of each form. The factors susceptible to induce a majority of a given conformation are written in bold characters. Others, such as PI(4,5)P₂ in the case of HIV-MA, are only able to (slightly) displace the equilibrium, even at a saturating concentration (Aa).

Figure 4

Models for retroviral Gag membrane binding. Aa and Ba: formation of Gag dimers, association on gRNA. Ab: inhibition of HIV-MA membrane binding by gRNA. Ac: removal of gRNA resulting from competition between gRNA and PI(4,5)P2 for HIV-MA binding. Ad: Stabilization of the [R] conformation of MA by interaction with PI(4,5)P2, Gag trimerization, stabilization of membrane anchoring by PS, lateral targeting of Gag to assembly microdomains. Bb: Binding of MLV-MA to PI(4,5)P2. Bc: Secondary binding of MLV-MA to PS, stabilization the MA [R] conformation. Bd: lateral targeting of Gag to assembly microdomains.