| dc.description | The fusogenic reoviruses are the only nonenveloped viruses known to induce cell-cell fusion, which they accomplish through a distinct class of viral nonstructural, membrane fusion-inducing proteins referred to as the Fusion-Associated Small Transmembrane (FAST) proteins. The factor responsible for the unusual fusogenic phenotype of baboon reovirus was identified as the 15-kDa product (p15) of the 5'-open reading frame of the bicistronic S4 genome segment. As p15 shares no significant overall sequence similarity with other FAST proteins and contains a unique repertoire and arrangement of sequence-predicted structural and functional motifs, p15 was designated as a novel member of the FAST protein family. Topological analysis indicated that p15 is a type 111 (Nexo/Ccyt) bitopic membrane protein that not only translocates the smallest ectodomain (about 20 amino acids) of any known viral fusion protein, but the p15 ectodomain also lacks a hydrophobic fusion peptide---an essential motif in virtually all other fusogenic proteins. The function of the p15 ectodomain depends on the presence of two atypical features, namely an N-terminal myristate moiety and a short polyproline helix (residues 10--15). A membrane-proximal, cytoplasmic polybasic motif was shown to contribute to p15 fusogenicity independent of its potential contribution to p15 topogenesis. A hydrophobic sequence present within the p15 endodomain is hypothesized to serve as a fusion-promoting motif, flanked by residues (comprising the 'FLX' region) exhibiting similarity to the externalized 'fusion peptides' of other FAST proteins. The FLX motifs could be functionally exchanged among the different FAST proteins and thus, are postulated to represent mechanistically-equivalent fusogenic regions. A model for p15-mediated membrane fusion is proposed in which p15 initiates membrane merger through perturbations of primarily the donor membrane. Unlike the current models of enveloped virus-mediated membrane fusion, p15 is neither predicted to be held in a metastable state, nor to undergo triggered conformational rearrangements that release energy harnessed to drive lipid bilayer mixing. These fundamental differences in the proposed mechanism of p15 action with respect to the fusion proteins of enveloped viruses may reflect the freedom that this nonstructural, 'non-essential' viral protein has had, outside of a receptor-binding constraint, to evolve a minimal fusogenic structure. | en_US |
