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Elife. 2017 Sep 16;6. pii: e28671. doi: 10.7554/eLife.28671.

Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase.

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Department of Biochemistry, Center for Biophysics and Computational Biology, University of Illinois at Urbana-Champaign, Urbana, United States.
Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, United States.
Department of Cell Biology, Emory University School of Medicine, Atlanta, United States.


From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the plasma membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is important in cellular signaling, but its mechanism remains incompletely understood. Using MD simulations coupled with experimental assays, we show that the surface hydrophilic transmembrane cavity exposed to the lipid bilayer on the fungal scramblase nhTMEM16 serves as the pathway for both lipid translocation and ion conduction across the membrane. Ca2+ binding stimulates its open conformation by altering the structure of transmembrane helices that line the cavity. We have identified key amino acids necessary for phospholipid scrambling and validated the idea that ions permeate TMEM16 Cl- channels via a structurally homologous pathway by showing that mutation of two residues in the pore region of the TMEM16A Ca2+-activated Cl- channel convert it into a robust scramblase.


biophysics; computational biology; electrophysiology; membrane transport; molecular simulation; mutagenesis; none; phospholipid scrambling; structural biology; systems biology

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