Development of membrane-insertable lipid scrambling peptides: A time-resolved small-angle neutron scattering study.

Phospholipid transbilayer movement (flip-flop) in the plasma membrane is regulated by membrane proteins to maintain cell homeostasis and interact with other cells. The promotion of flip-flop by phospholipid scramblases causes the loss of membrane lipid asymmetry, which is involved in apoptosis, blood coagulation, and viral infection. Therefore, compounds that can artificially control flip-flop in the plasma membrane are of biological and medical interest. Here, we have developed lipid scrambling transmembrane peptides that can be inserted into the membrane. Time-resolved small-angle neutron scattering measurements revealed that the addition of peptides containing a glutamine residue at the center of the hydrophobic sequence to lipid vesicles induces the flip-flop of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine. Peptides without the glutamine residue had no effect on the flip-flop. Because the glutamine-containing peptides exhibited scramblase activity in monomeric form, the polar glutamine residue would be exposed to the hydrocarbon region of the membrane, perturbing the membrane and promoting the lipid flip-flop. These scrambling peptides would be valuable tools to regulate lipid flip-flop in the plasma membrane.