Abstract
Virus assembly and maturation proceed through the programmed operation of molecular switches, which trigger both local and global structural rearrangements to produce infectious particles. HIV-1 contains an assembly and maturation switch that spans the C-terminal domain (CTD) of the capsid (CA) region and the first spacer peptide (SP1) of the precursor structural protein, Gag. The crystal structure of the CTD-SP1 Gag fragment is a goblet-shaped hexamer in which the cup comprises the CTD and an ensuing type II β-turn, and the stem comprises a 6-helix bundle. The β-turn is critical for immature virus assembly and the 6-helix bundle regulates proteolysis during maturation. This bipartite character explains why the SP1 spacer is a critical element of HIV-1 Gag but is not a universal property of retroviruses. Our results also indicate that HIV-1 maturation inhibitors suppress unfolding of the CA-SP1 junction and thereby delay access of the viral protease to its substrate.
Highlights
And maturation of HIV-1 and other retroviruses is driven by the viral structural polyprotein, Gag, which consists of a series of independently folding domains, called MA, CA, and NC
We found that purified C-terminal domain (CTD)-SP1 protein assembled in vitro into flat sheets with the subunits organized into a hexagonal lattice with the expected unit cell spacing of the CTD layer of the immature Gag lattice (~74 A ) (Wright et al, 2007 ) (Figure 1— figure supplement 1)
Our post hoc analysis is that these crystals were rare because the CA-SP1 junction residues had to fold and become ordered during crystallization
Summary
And maturation of HIV-1 and other retroviruses is driven by the viral structural polyprotein, Gag, which consists of a series of independently folding domains, called MA (matrix), CA (capsid), and NC (nucleocapsid) (reviewed in Bush and Vogt, 2014; Ganser-Pornillos et al, 2012; Lingappa et al, 2014). Gag makes a spherical, immature capsid shell that packages the viral genome, directs interactions with the plasma membrane to promote envelopment, and recruits cellular machinery to release the new virus particle from the host cell. The Gag shell has hexagonal paracrystalline lattice symmetry, wherein the central CA region makes two layers of interactions through its two domains (NTD and CTD, for N-terminal and C-terminal domain). Gag is cleaved by the viral protease at specific sites. This results in disassembly of the Gag shell and release of new structural proteins, which rearrange into the mature, infectious virion. The genome is repackaged inside a cone-shaped capsid made up of the CA protein, with the NTD forming hexameric or pentameric rings that are connected by the CTD
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