Abstract
The CA (capsid) domain of immature HIV-1 Gag and the adjacent spacer peptide 1 (SP1) play a key role in viral assembly by forming a lattice of CA hexamers, which adapts to viral envelope curvature by incorporating small lattice defects and a large gap at the site of budding. This lattice is stabilized by intrahexameric and interhexameric CA-CA interactions, which are important in regulating viral assembly and maturation. We applied subtomogram averaging and classification to determine the oligomerization state of CA at lattice edges and found that CA forms partial hexamers. These structures reveal the network of interactions formed by CA-SP1 at the lattice edge. We also performed atomistic molecular dynamics simulations of CA-CA interactions stabilizing the immature lattice and partial CA-SP1 helical bundles. Free energy calculations reveal increased propensity for helix-to-coil transitions in partial hexamers compared to complete six-helix bundles. Taken together, these results suggest that the CA dimer is the basic unit of lattice assembly, partial hexamers exist at lattice edges, these are in a helix-coil dynamic equilibrium, and partial helical bundles are more likely to unfold, representing potential sites for HIV-1 maturation initiation.
Highlights
The CA domain of immature HIV-1 Gag and the adjacent spacer peptide 1 (SP1) play a key role in viral assembly by forming a lattice of CA hexamers, which adapts to viral envelope curvature by incorporating small lattice defects and a large gap at the site of budding
Our analysis shows that Gag dimers are the basic assembly unit of the HIV-1 particle, lattice edges are partial hexamers, and partial hexamers are prone to structural changes allowing protease to cut Gag
Our results suggest that the basic unit of immature HIV-1 assembly is a Gag dimer and partial CASP1 helical bundles are present at the edges of the assembled lattice and may be substrates for initiation of maturation
Summary
The CA (capsid) domain of immature HIV-1 Gag and the adjacent spacer peptide 1 (SP1) play a key role in viral assembly by forming a lattice of CA hexamers, which adapts to viral envelope curvature by incorporating small lattice defects and a large gap at the site of budding. Amphipathic helices formed by the C-terminal residues of CACTD and the N-terminal residues of SP1 junction assemble into a sixhelix bundle (6HB), thereby imposing hexagonal order on the CA domains, via classical knobs-in-holes packing mediated by exposed hydrophobic side chains, as seen in coiled coils [9, 10] In combination, these relatively weak interactions give rise to a very dynamic, reversible assembly process that prevents the assembling lattice from becoming trapped in kinetically unfavorable states [11].
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