Two subfamilies comprise the family of exogenous retroviruses: the orthoretroviruses, made up of six genera (␣-to ε-retroviruses and lentiviruses), and the spumaretroviruses, comprised exclusively of the foamy virus (FV) genus (33). There are major differences in the replication strategies between both subfamilies which are responsible for this distinction (32, 48).On a structural level, this is reflected by very unusual FV Gag proteins, which are not cleaved by the viral protease (PR) into matrix (MA), capsid (CA), and nucleocapsid (NC) subunits (32, 48). Instead, the FV PR cleaves only a small peptide (p3 in case of the prototypic FV [PFV]) from the C terminus of FV Gag proteins (17,44). This C-terminal cleavage is essential for FV replication (13, 76). Complete proteolytic cleavage of the capsid occurs most likely in the process of uncoating after fusion with new cells and uses unconventional cleavage sites (19,28).The FV Env protein constitutes another peculiarity. In contrast to orthoretroviral Envs, which are-with surface (SU) and transmembrane (TM) subunits-bipartite in nature (22), the FV Env is a tripartite protein that bears, in addition to SU and TM, a membrane-spanning type II and particle-associated leader peptide (LP), which has a mass of 18 kDa in the case of PFV (30,31). The LP of the PFV Env protein is oligo-ubiquitinated and appears to perform functions in viral replication which are confined to Gag in orthoretroviruses (62).FV capsids do not bud spontaneously from the plasma membrane and do not naturally form virus-like particles (VLPs) (16). They require the presence of authentic Env for cellular export (45). Furthermore, pseudotyping of unmodified FV capsids with other (viral) glycoproteins appears to be impossible (45). On the other hand, pseudotyping of other viral capsids by FV Env and, in particular, by mutants in the ubiquitination sites of LP, is very efficient (72). In FVs, domains on the side of Env particularly located in LP are essential for a specific contact with Gag (31).With Gag, the situation is less clear. Deletion studies suggested that approximately the first 100 amino acids of the 648 residues of PFV Gag are essential to mediate the specific Env interaction (6).Some other domains in the PFV Gag protein have been characterized. A cytoplasmic targeting and retention signal (CTRS) is located in the N-terminal domain (amino acids [aa] 43 to 60) (12). A late (L) domain, specified by the motif PSAP (aa 284 to 287) interacts with the cellular export machinery (vacuolar protein sorting [VPS]) via TSG101 for complete release of virus particles from the plasma membrane (41, 61). However, ubiquitination of PFV Gag has not been found, while ubiquitination is a common feature of orthoretroviral capsids upon interaction with the VPS machinery (46,77).Four coiled-coil (CC) motifs (CC1 to CC4) are predicted to be present in PFV Gag. The CC1 motif is very N-terminally (aa 4 to 19) located, and mutations in this region indicated an interaction domain with Env (29). The CC2 (aa 133 to 146)...
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