Protein-induced fusion can be modulated by target membrane lipids through a structural switch at the level of the fusion peptide

Regulatory features of protein-induced membrane fusion are largely unclear, particularly at the level of the fusion peptide. Fusion peptides being par t of larger protein complexes, such investigations are met with technical l imitations. Here, we show that the fusion activity of influenza virus or Go lgi membranes is strongly inhibited by minor amounts of (lyso)lipids when p resent in the target membrane but not when inserted into the viral or Golgi membrane itself. To investigate the underlying mechanism, we employ a memb rane-anchored peptide system and show that fusion is similarly regulated by these lipids when inserted into the target but not when present in the pep tide-containing membrane, Peptide-induced fusion is regulated by a reversib le switch of secondary structure from a fusion-permissive alpha-helix to a nonfusogenic beta-sheet. The "on/off" activation of this switch is governed by minor amounts of (lyso)-phospholipids in targets, causing a drop in cu- helix and a dramatic increase in beta-sheet contents. Concomitantly, fusion is inhibited, due to impaired peptide insertion into the target membrane. Our observations in biological fusion systems together with the model studi es suggest that distinct lipids in target membranes provide a means for reg ulating membrane fusion by causing a reversible secondary structure switch of the fusion peptides.