Abstract
HIV-1 Gag polyprotein orchestrates the assembly of viral particles. Its C-terminus consists of the nucleocapsid (NC) domain that interacts with nucleic acids, and p1 and p6, two unstructured regions, p6 containing the motifs to bind ALIX, the cellular ESCRT factor TSG101 and the viral protein Vpr. The processing of Gag by the viral protease subsequently liberates NCp15 (NC-p1-p6), NCp9 (NC-p1) and NCp7, NCp7 displaying the optimal chaperone activity of nucleic acids. This review focuses on the nucleic acid binding properties of the NC domain in the different maturation states during the HIV-1 viral cycle.
Highlights
The HIV-1 Gag protein coordinates all major steps in virion assembly.Gag comprises three ordered domains, namely the matrix (MA), the capsid (CA) and the nucleocapsid (NC) domains, which are connected by two linkers, p2 and p1(Figure 1A). p6 was shown to be structured under membranous solution conditions [1]; p1–p6 was shown to be mostly disordered in the context of the C-terminal (Cter) part of Gag and to present regions that transiently adopt α-helical structures [2]
The structural and dynamic data discussed here highlight several aspects of NC-nucleic acid (NA) interactions: 1) ZK2 interacts with unpaired guanines, the preferred substrate of NC, and is more prone to do so than ZK1; 2) NC orients on NA chains with a definite polarity, depending on the nature of the NA (DNA or RNA); 3) the dynamics of the two ZKs are remarkably different, due to their different localizations in the sequence rather than to their slightly different compositions in amino acids
These biophysical properties explain a number of observations reported in the literature, and the paragraph is devoted to this point
Summary
The HIV-1 Gag (group-specific antigen) protein coordinates all major steps in virion assembly. HIV-1 Gag molecules exist as monomers or low-order multimers in the cell cytosol and only form higher-order multimers after binding to the plasma membrane [3], nucleating the assembly of thousands of Gag molecules into an immature virion [4]. The first cleavage by the HIV-1 protease occurs between MA-CA-p2 and NC-p1–p6, thereby liberating NCp15. The ability of the protease to achieve ordered Gag processing at specific cleavage sites, which display little to no Virusesidentity, 2020, 12, 1109 of 20 that sequence primarily originates from the conformational dynamics of the protease flaps cover its active site and that are involved in substrate recognition [29].
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