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Structural Basis of Lipid Scrambling and Ion Conduction by TMEM16 Scramblases

The plasma membrane of eukaryotic cells is asymmetric, with polar and charged lipids sequestered to the inner leaflet when the cell is at rest. Activation of phospholipid scramblases rapidly collapses this asymmetry and externalizes negatively charged phosphatidylserine lipids, activating extracellular signaling networks that control processes such as apoptosis, blood coagulation, membrane fusion and repair. The TMEM16 family is comprised of Ca2+‐dependent Cl− channels and phospholipid scramblases with non‐selective ion channel activity. Structural and functional analyses of TMEM16 scramblases identified a membrane‐exposed hydrophilic groove that serves as a dual translocation pathway for ions and lipids. The mechanisms underlying Ca2+‐dependent gating of TMEM16 scramblases/non‐selective channels, lipid permeation and the emergence of their ion conduction pore remain poorly understood. We used cryo‐electron microscopy to determine the structures of a fungal scramblase/non‐selective channel from Aspergillus fumigatus, afTMEM16, reconstituted in lipid nanodiscs in the presence and absence of Ca2+. These structures reveal that Ca2+ binding induces a global rearrangement of the transmembrane and cytosolic regions, resulting in opening of the lipid permeation pathway by way of rearrangements of TM4 and TM6. The structures of the scramblase/nanodisc complex in the presence and absence of Ca2+ show that the scramblases induce a pronounced distortion of the surrounding membrane: the outer leaflet is bent along the dimer axis of the protein and the membrane is thinned near the opened lipid translocation pathway thereby facilitating transbilayer lipid movement.