Abstract
Understanding the molecular mechanisms of retroviral assembly has been a decades-long endeavor. With the recent discovery of inositol hexakisphosphate (IP6) acting as an assembly co-factor for human immunodeficiency virus (HIV), great strides have been made in retroviral research. In this review, the enzymatic pathways to synthesize and metabolize inositol phosphates (IPs) relevant to retroviral assembly are discussed. The functions of these enzymes and IPs are outlined in the context of the cellular biology important for retroviruses. Lastly, the recent advances in understanding the role of IPs in retroviral biology are surveyed.
Highlights
Understanding the molecular mechanisms of retroviral assembly has been a decades-long endeavor
The mass of total cellular labeled inositol phosphates (IPs) can be measured by PAGE separation as above, and the percent of the radioactivity in virus-like particles (VLPs) is used to back-calculate the mass incorporated in the VLPs [46]
Through complete depletion of these small molecules via exogenous expression of Multiple inositol polyphosphate phosphatase-1 (MINPP1) in the context of an inositol pentakisphosphate 2-kinase (IPPK)-knocking out (KO), human immunodeficiency virus (HIV)-infected cells were found unable to release any infectious virions. This defect was attributed to the inability of the virus to assemble or bud since full-length Gag was still produced at normal levels in the IPPK-KO/MINPP1+
Summary
The six molecules of Gag are held together in large part by a six-helix bundle (6HB), with each helix being formed by the last few residues of the CACTD plus most of the 14-amino acid residue “spacer” domain, called SP1 [4] The lattice of these hexamers is stabilized by CANTD -CANTD dimer and trimer interactions. The hexamer of MA trimers shifts to a more tightly packed lattice creating larger regions of the viral membrane not occupied by MA in the mature virion This restructuring is presumed to allow for Env conformational changes and clustering of many Env trimers in preparation to bind host receptor CD4 [17–19]. Further delineating the site of IP6 activity on assembly, IP6 stimulated CACTD SP1 to form flat crystals which were solved by x-ray crystallography by the Pornillos lab This structure showed IP6 is coordinated by two rings of six lysines (K290 & K359) at the CACTD six-helix bundle interface (Figure 1C).
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