The transbilayer movement of lipids (lipid flip/flop)
Transbilayer lipid translocation, termed flip/flop, is essential for various biological processes within the cell. For example, lipid translocation is important at endoplasmic reticulum or bacterial membranes. There, lipids synthesized at the cytoplasmic leaflet translocate to the exoplasmic leaflet to balance the amount of lipid molecules in both leaflets during membrane biogenesis. Lipid flip involves the energetically unfavorable removal of the polar lipid headgroups from hydrogen-bonded lipid networks and their transfer across the hydrophobic acyl chain region. However, the mechamism of flip is unclear and a dedicated biogenic lipid flippase has not yet been identified.
We study the lipid flippase activity of synthetic TMDs, like ‘LV-TMDs’. LV-peptides were designed from low-complexity sequences containing amino acids of different conformational preference and charge. We find that the variable backbone sequence of these TMDs defines their ability to flip lipids with different headgroups. A new model of lipid flip/flop is forwarded where a dynamic flipogenic TMD disorders the surrounding membrane to allow for lipid translocation.
Further, it appears as if SNARE proteins could be among an unspecified set of proteins that have been postulated to carry out biogenic lipid flip at the endoplasmic reticulum in addition to their fusogenic function.
Future investigations may provide a deeper understanding of how the dynamics and self-interaction of a TMD could define its ability to catalyze translocation of lipids with different headgroups.