Abstract
The small cellular molecule inositol hexakisphosphate (IP6) has been known for ~20 years to promote the in vitro assembly of HIV-1 into immature virus-like particles. However, the molecular details underlying this effect have been determined only recently, with the identification of the IP6 binding site in the immature Gag lattice. IP6 also promotes formation of the mature capsid protein (CA) lattice via a second IP6 binding site, and enhances core stability, creating a favorable environment for reverse transcription. IP6 also enhances assembly of other retroviruses, from both the Lentivirus and the Alpharetrovirus genera. These findings suggest that IP6 may have a conserved function throughout the family Retroviridae. Here, we discuss the different steps in the viral life cycle that are influenced by IP6, and describe in detail how IP6 interacts with the immature and mature lattices of different retroviruses.
Highlights
Introduction the Role ofIP6 in Immature andAll retroviruses code for a multidomain structural protein Gag (Figure 1A)
It is reasonable to assume that the striking structural feature of 12 lysines coordinating a negatively charged molecule is widely conserved within lentiviruses, as conserved lysine residues can be observed at identical positions in Gag of other members of this genus, including HIV-2, Simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV), and BIV (Figure 3)
Right: model of IP6 binding in the RSV CANC hexamer, derived from a structure solved by cryo-ET and subtomogram averaging
Summary
All retroviruses code for a multidomain structural protein Gag (Figure 1A). Late in the viral life cycle, Gag traffics to the inner leaflet of the plasma membrane where the. Following release of the immature virus particle from the infected cell (Figure 1B, step 3), the viral protease (PR) cleaves Gag, liberating CA and other Gag domains (Figure 1B, step 4) In this process, termed maturation, all immature CA–CA interactions are broken and an entirely new set of interactions between CA proteins form the mature lattice, consisting of CA hexamers and pentamers, resulting in the mature core ( referred to as the capsid). We discuss the importance of vealed the involvement of the small negatively charged molecule inositol hexakisphosphate (IP6) in all of these steps of the HIV-1 life cycle, supporting its key structural and functional role in regulating HIV-1 assembly, maturation, and reverse transcription. IP6 for other retrovirus genera, indicating an evolutionarily conserved structural role of this molecule
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