Model of the role of the FLiPS motif in membrane fusion.

<p>Depicted is a FAST protein structure based on composite NMR structures of p14 ectodomain and transmembrane domain conformers, and a p15 endodomain FLiPS conformer. Linker regions and the extended C-terminal tail (which is intrinsically disordered) are modelled as unstructured loops. Residues are colour-coded: green, hydrophobic; blue, polar/charged; orange, neutral. Fusion peptide motifs in FAST protein ectodomains are predicted to combine with essential residues in the external interfacial region of the transmembrane domain [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1004962#ppat.1004962.ref034" target="_blank">34</a>] to alter membrane curvature leading to dimple formation and merger of outer bilayer leaflets creating a presumed hemifusion intermediate (left). Negative curvature stresses in the outer monolayer create corresponding positive curvature stresses in the inner monolayer, rendering this transient intermediate energetically unfavorable and likely to revert to two planar bilayers. However, FLiPS partitioning into regions of increasing positive curvature, such as those in the inner monolayer at the base of the stalk-like hemifusion intermediate, would stabilize curvature stresses and promote further positive curvature making the forward reaction to pore formation (right) a more energetically favorable means to resolve the unstable hemifusion intermediate curvature. POPC molecules show insertion of the FLiPS into a hydrophobic defect generated by curvature stresses forcing apart lipid headgroups.