ABSTRACT
TMEM16F is a Ca2+-activated phospholipid scramblase in the TMEM16 family of membrane proteins. Unlike other TMEM16s exhibiting a membrane-exposed hydrophilic groove that serves as a translocation pathway for lipids, the experimentally determined structures of TMEM16F shows the groove in a closed conformation even under conditions of maximal scramblase activity. Here we describe the analysis of ∼400 µs all-atom ensemble molecular dynamics (MD) simulations of the TMEM16F dimer that revealed an allosteric mechanism leading to an open-groove state of the protein that is competent for lipid scrambling. The grove opens into a continuous hydrophilic conduit that is highly similar in structure to that seen in other activated scramblases. The allosteric pathway connects this opening to an observed destabilization of the Ca2+ ion bound at the distal site near the dimer interface, to the dynamics of specific protein regions that produces the open-groove state seen in our MD simulations to scramble phospholipids.
Competing Interest Statement
The authors have declared no competing interest.
