1.G.13.2.1
The p15 fusion-associated small transmembrane (FAST) protein is a nonstructural viral protein that induces cell-cell fusion and syncytium formation (Top et al. 2012). The small, myristoylated N-terminal ectodomain of p15 lacks any of the defining features of a typical viral fusion protein. NMR and CD spectroscopy indicated that this small fusion module comprises a left-handed polyproline type II (PPII) helix flanked by small, unstructured N- and C-termini (PDB# 2MNS_A). Individual prolines in the 6-residue proline-rich motif are tolerant to alanine substitutions, but multiple substitutions that disrupt the PPII helix eliminate cell-cell fusion activity. A synthetic p15 ectodomain peptide induces lipid mixing between liposomes. Lipid mixing, liposome aggregation, and stable peptide-membrane interactions are all dependent on both the N-terminal myristate and the presence of the PPII helix. A model for the mechanism of action of this viral fusion peptide, whereby the N-terminal myristate mediates initial, reversible peptide-membrane binding that is stabilized by subsequent amino acid-membrane interactions. These interactions induce a biphasic membrane fusion reaction, with peptide-induced liposome aggregation representing a distinct, rate-limiting event that precedes membrane merger. The PPII helix may function to force solvent exposure of hydrophobic amino acid side chains in the regions flanking the helix to promote membrane binding, apposition, and fusion (Top et al. 2012).  A fusion-inducing lipid packing sensor (FLiPS) in the cytosolic endodomain in the p15 fusion-associated small transmembrane (FAST) protein is essential for pore formation during cell-cell fusion and syncytiogenesis (Read et al. 2015).