Date of Original Version
To advance mechanistic understanding of membrane-associated peptide folding and insertion, we have studied the kinetics of three single tryptophan pHLIP (pH-Low Insertion Peptide) variants, where tryptophan residues are located near the N terminus, near the middle, and near the inserting C-terminal end of the pHLIP transmembrane helix. Single-tryptophan pHLIP variants allowed us to probe different parts of the peptide in the pathways of peptide insertion into the lipid bilayer (triggered by a pH drop) and peptide exit from the bilayer (triggered by a rise in pH). By using pH jumps of different magnitudes, we slowed down the processes and established the intermediates that helped us to understand the principles of insertion and exit. The obtained results should also aid the applications in medicine that are now entering the clinic.
Gregory Slaybaugh, Dhammika Weerakkody, Donald M. Engelman, Oleg A. Andreev, Yana K. Reshetnyak. Kinetics of pHLIP peptide insertion into and exit from a membrane. Proceedings of the National Academy of Sciences Jun 2020, 117 (22) 12095-12100; DOI: 10.1073/pnas.1917857117