Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM

Stepwise activation mechanism of the scramblase nhTMEM16 revealed by cryo-EM

Blog Article

Scramblases catalyze the movement of lipids between both leaflets of a bilayer.Whereas the X-ray structure of the protein nhTMEM16 has previously revealed the architecture of a here Ca2+-dependent lipid scramblase, its regulation mechanism has remained elusive.Here, we have used cryo-electron microscopy and functional assays to address this question.

Ca2+-bound and Ca2+-free conformations of nhTMEM16 in detergent and lipid nanodiscs illustrate the interactions with its environment and they reveal the conformational changes click here underlying its activation.In this process, Ca2+ binding induces a stepwise transition of the catalytic subunit cavity, converting a closed cavity that is shielded from the membrane in the absence of ligand, into a polar furrow that becomes accessible to lipid headgroups in the Ca2+-bound state.Additionally, our structures demonstrate how nhTMEM16 distorts the membrane at both entrances of the subunit cavity, thereby decreasing the energy barrier for lipid movement.