Lipids and ions traverse the membrane by the same physical pathway in the nhTMEM16 scramblase
Abstract
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.
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Author details
Funding
National Institutes of Health (R01-GM086749)
- Emad Tajkhorshid
National Institutes of Health (U54- GM087519)
- Emad Tajkhorshid
National Institutes of Health (P41-GM104601)
- Emad Tajkhorshid
National Institutes of Health (R01-EY0114852)
- H Criss Hartzell
National Institutes of Health (R01-AR067786)
- H Criss Hartzell
National Science Foundation (MCA06N060)
- Emad Tajkhorshid
National Institutes of Health (R01-GM123455)
- Emad Tajkhorshid
Muscular Dystrophy Association (Research Grant)
- H Criss Hartzell
National Centre for Supercomputing Applications (Blue Waters)
- Emad Tajkhorshid
This research is supported by grants from the National Institutes of Health R01-GM086749, R01-GM123455, U54- GM087519, and P41-GM104601 to ET, and R01-EY0114852 and R01-AR067786 to HCH, and a grant from the Muscular Dystrophy Foundation to HCH. Simulations in this study have been performed using allocations at National Science Foundation Supercomputing Centers (XSEDE grant number MCA06N060), and at the NCSA Blue Waters.
Reviewing Editor
- Nir Ben-Tal, Tel Aviv University, Israel
Publication history
- Received: May 18, 2017
- Accepted: September 8, 2017
- Accepted Manuscript published: September 16, 2017 (version 1)
- Version of Record published: October 4, 2017 (version 2)
Copyright
© 2017, Jiang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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