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Elife. 2019 Feb 21;8. pii: e44364. doi: 10.7554/eLife.44364.

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

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Department of Biochemistry, University of Zurich, Zurich, Switzerland.
Department of Structural Biology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands.


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 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 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.


S. cerevisiae; TMEM16; activation mechanism; biochemistry; chemical biology; cryo-EM; lipid scrambling; membrane interaction; molecular biophysics; structural biology

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