HIV-1 Gag specificity for PIP2 is regulated by macromolecular electric properties of both protein and membrane local environments

• Published in: Biochimica et biophysica acta. Biomembranes 2023-06, Vol.1865 (5), p.184157-184157, Article 184157
• Main Authors: Socas, L.B.P., Ambroggio, E.E.
• Format: Article
• Language: English
• Subjects: HIV-1 Gag matrix domain; Human immunodeficiency virus; PIP2; Protein-membrane interaction; Protein-RNA interaction
• ISSN: 0005-2736; 1879-2642
• DOI: 10.1016/j.bbamem.2023.184157

HIV-1 assembly occurs at the plasma membrane, with the Gag polyprotein playing a crucial role. Gag association with the membrane is directed by the matrix domain (MA), which is myristoylated and has a highly basic region that interacts with anionic lipids. Several pieces of evidence suggest that the presence of phosphatidylinositol-(4,5)-bisphosphate (PIP2) highly influences this binding. Furthermore, MA also interacts with nucleic acids, which is proposed to be important for the specificity of GAG for PIP2-containing membranes. It is hypothesized that RNA has a chaperone function by interacting with the MA domain, preventing Gag from associating with unspecific lipid interfaces. Here, we study the interaction of MA with monolayer and bilayer membrane systems, focusing on the specificity for PIP2 and on the possible effects of a Gag N-terminal peptide on impairing the binding for either RNA or membrane. We found that RNA decreases the kinetics of the protein association with lipid monolayers but has no effect on the selectivity for PIP2. Interestingly, for bilayer systems, this selectivity increases in presence of both the peptide and RNA, even for highly negatively charged compositions, where MA alone does not discriminate between membranes with or without PIP2. Therefore, we propose that the specificity of MA for PIP2-containing membranes might be related to the electrostatic properties of both membrane and protein local environments, rather than a simple difference in molecular affinities. This scenario provides a new understanding of the regulation mechanism, with a macromolecular view, rather than considering molecular interactions within a ligand-receptor model. [Display omitted] •The MA domain of the HIV-1 GAG finely regulates the formation of virions at the PM of infected cells.•MA myristoylation and interaction with RNA regulate this process.•The presence of traces of the PIP2 lipid competes with RNA downregulation.•MA-derived peptides compete with MA for nucleic acid binding and its membrane interaction.•This is compelling evidence that MA membrane binding depends on the local dielectric environment.