The cryo-EM structures of XKR9 define the architecture and caspase-mediated activation of a protein family that is involved in the exposure of phosphatidylserine during apoptosis leading to the engulfment of apoptotic cells by macrophages.
The amino acids that are necessary for phospholipid scrambling by ANO6/TMEM16F can, via domain swapping, confer scrambling activity to the chloride ion channel ANO1 that normally does not scramble phospholipids.
While activated by a common mechanism, both functions in TMEM16F - lipid scrambling and ion conduction - are likely mediated by alternate protein conformations that are at equilibrium in the ligand-bound state.
A concerted approach employing equilibrium and biased molecular simulations, electrophysiology, mutagenesis, and functional assays reveals, in atomic details, the mechanism and pathway for transport of phospholipids and ions by a lipid scramblase.
Structures of a TMEM16 phospholipid scramblase reveal that its Ca2+-dependent activation entails global conformational changes and how these rearrangements affect the membrane to enable transbilayer lipid transfer.
Computation and experiment together demonstrate that nonspecific membrane–protein interactions could regulate transmembrane protein function and suggest that covalent linkers can be an integral component of the sensing apparatus.