A newly characterized calcium-activated chloride channel has been implicated in the immune system of Drosophila, shedding light on an enigmatic family of transmembrane proteins that are ubiquitous in nature.
Single-particle cryo-EM and electrophysiology studies of the chloride channel TMEM16A reveals the structural basis for anion conduction and uncover its relationship to lipid scramblases of the same family.
A functional link between representative family members of the CLCA channel regulator family and TMEM16 channels suggests that these protein families may cooperate in influencing multiple homeostatic and disease physiologies.
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.