Bending membranes along distinct pathways of protein assembly.

Abstract

Membrane remodeling is almost universally dependent on the work of self-assembled proteins. In viral budding, protein coat components can exploit distinct mechanisms to drive bending of the membrane from its preferred, relatively flat state. During HIV-1 infection, the retroviral Gag proteins can work to either scaffold the membrane or locally induce changes in curvature through insertion. While both mechanisms can operate simultaneously, the scaffolding will be dependent on assembly of higher-order Gag lattices. The extent to which the protein coat assembly precedes recruitment to the membrane will thus impact both membrane bending and further assembly, thereby tuning successful budding out of the cell. In HIV-1 infected cells, the arrival of Gag to the membrane may proceed via monomers or larger oligomers. We construct models of HIV-1 Gag lattice assembly using structure-resolved reaction-diffusion that allow us to quantify mechanisms of assembly in solution and on the membrane. Using a continuum membrane model, we can then couple distinct assembly paths to the corresponding energetic cost of membrane budding. We can further quantify how mutations to weaken either membrane bending mechanism would impair proper budding. Finally, we discuss when the stability and kinetics of the Gag lattice contacts can support lattice remodeling on the budded virion, which is critical for viral maturation.