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Molecular mechanisms of ion conduction and ion selectivity in TMEM16 lipid scramblases

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  • Andrei Y. Kostritskii

    (Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich
    Institute of Clinical Pharmacology, RWTH Aachen University
    Department of Physics, RWTH Aachen University)

  • Jan-Philipp Machtens

    (Institute of Biological Information Processing (IBI-1), Molekular- und Zellphysiologie, and JARA-HPC, Forschungszentrum Jülich
    Institute of Clinical Pharmacology, RWTH Aachen University)

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.

Suggested Citation

  • Andrei Y. Kostritskii & Jan-Philipp Machtens, 2021. "Molecular mechanisms of ion conduction and ion selectivity in TMEM16 lipid scramblases," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22724-w
    DOI: 10.1038/s41467-021-22724-w
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    Cited by:

    1. Maria E. Falzone & Zhang Feng & Omar E. Alvarenga & Yangang Pan & ByoungCheol Lee & Xiaolu Cheng & Eva Fortea & Simon Scheuring & Alessio Accardi, 2022. "TMEM16 scramblases thin the membrane to enable lipid scrambling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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