Abstract
TMEM16 lipid scramblases transport lipids and also operate as ion channels with highly variable ion selectivities and various physiological functions. However, their molecular mechanisms of ion conduction and selectivity remain largely unknown. Using computational electrophysiology simulations at atomistic resolution, we identified the main ion-conductive state of TMEM16 lipid scramblases, in which an ion permeation pathway is lined by lipid headgroups that directly interact with permeating ions in a voltage polarity-dependent manner. We found that lipid headgroups modulate the ion-permeability state and regulate ion selectivity to varying degrees in different scramblase isoforms, depending on the amino-acid composition of the pores. Our work has defined the structural basis of ion conduction and selectivity in TMEM16 lipid scramblases and uncovered the mechanisms responsible for the direct effects of membrane lipids on the conduction properties of ion channels.
Highlights
TMEM16 lipid scramblases transport lipids and operate as ion channels with highly variable ion selectivities and various physiological functions
The transmembrane voltage was set by a charge imbalance, which was sustained by the Computational Electrophysiology (CompEL) algorithm that swaps ions and water molecules once ion permeation has taken place[35]
NhTMEM16 conducts ions through a structured but still dynamic proteolipidic pore, which is lined by lipid headgroups and the residues of the subunit cavity
Summary
TMEM16 lipid scramblases transport lipids and operate as ion channels with highly variable ion selectivities and various physiological functions. In the fully activated Ca2+-bound state, each protomer forms a so-called subunit cavity (i.e. a membranespanning hydrophilic groove) that is exposed to the hydrophobic membrane environment (Fig. 1b) This unique topological feature has been assumed to underlie the lipid-scrambling mechanism by providing a pathway for polar lipid headgroups to move across the membrane. The “alternating porecavity” model[22] was suggested based on an intermediate, semiclosed conformation of the cavity that was observed in several cryo-EM structures of Ca2+-bound TMEM16 lipid scramblases[22,25,27,33] In this conformation, the extracellular part of the cavity is sealed from the membrane, so the structure was supposed to represent an ion (but not lipid) conductive state (Fig. 1c). Recent MD simulations support ion conduction through the proteolipidic pore[13], results of structural and functional studies[25,33] propose the intermediate semi-closed conformation as the main conductive state of TMEM16 lipid scramblases. Results from structural, functional, and computational studies have not yet reached a consensus on the mechanism of ion conduction in TMEM16 lipid scramblases
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