2.B.130.  The Transmembrane Alpha-helical Peptide FlipFlop (TAP-FF) Family  

Nakao and Nakano 2022 examined a large number of hydrophobic α-helical peptides with respect to their ability to catalyze te flipping of various lipids across membranes, and they found many (32) with this catalytic capacity, and many were catalytically active.  Kol et al. first evaluated the flop of fluorescent lipids using transmembrane peptides with a Leu-Ala repeat sequence and terminal X residues (X = Lys, His, or Trp) known as XALP55) (Table 1) in Nakao and Nakano 2022.  XALP peptides can be incorporated into PC membranes to form transmembrane α-helices. All XALP peptides increase the flop rate of phosphatidylglycerol (PG), and KALP and WALP peptides also promote PE flop.  The similar flop-promoting abilities of XALP peptides with varying flanking residues suggest that the mere presence of trans- membrane helices is important for phospholipid flip-flop promotion. Local perturbations in the vicinity of the helix may facilitate flip-flop. Langer et al. demonstrated that distinct α-helical peptides with membrane-spanning sequences composed of Leu, Leu-Val repeats, or Leu-Leu-Val repeats facilitate the flip of PC, PE, and PS58) (see Table 1). The highly dynamic helical backbone may disrupt lipid acyl chains and promote flip-flop Nakao and Nakano 2022.