TMEM16F is a dual ion channel and lipid scramblase that mediates the collapse of plasma membrane asymmetry by facilitating lipid cross-over from one leaflet to the other. A major example of how lipid scrambling has functional importance is the exposure of phosphatidylserine (PS) by TMEM16F in the plasma membrane of platelets, which initiates the blood clotting process. We conducted extensive coarse-grained molecular dynamics simulations to gain insight into how TMEM16F and other members of the TMEM16 protein family scramble lipids. This allowed us to dissect the roles of two of the main contributing factors to lipid scrambling: (1) protein-induced membrane thinning and (2) dilation of the hydrophilic groove between transmembrane helices 4 and 6 that functions as the main scrambling pathway. In agreement with a fluorescence polarization-based scrambling assay in live cells, we report that—within the context of complex lipid mixtures—TMEM16F selectively scrambles phosphatidylcholine (PC) and PS over phosphatidylethanolamine (PE).
Hilten et al. (Sun,) studied this question.