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Title: Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase

Abstract

Members of the TMEM16/ANO family of membrane proteins are Ca 2+-activated phospholipid scramblases and/or Cl - channels. A membrane-exposed hydrophilic groove in these proteins serves as a shared translocation pathway for ions and lipids. However, the mechanism by which lipids gain access to and permeate through the groove remains poorly understood. Here, we combine quantitative scrambling assays and molecular dynamic simulations to identify the key steps regulating lipid movement through the groove. Lipid scrambling is limited by two constrictions defined by evolutionarily conserved charged and polar residues, one extracellular and the other near the membrane mid-point. The region between these constrictions is inaccessible to lipids and water molecules, suggesting that the groove is in a non-conductive conformation. A sequence of lipid-triggered reorganizations of interactions between these residues and the permeating lipids propagates from the extracellular entryway to the central constriction, allowing the groove to open and coordinate the headgroups of transiting lipids.

Authors:
 [1];  [2];  [2]; ORCiD logo [2];  [2]; ORCiD logo [2]
  1. Cornell Univ., Ithaca, NY (United States). Weill Medical College; Korea Brain Research Inst. (KBRI), Daegu (Korea)
  2. Cornell Univ., Ithaca, NY (United States). Weill Medical College
Publication Date:
Research Org.:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); National Research Foundation of Korea (NRF)
OSTI Identifier:
1565677
Grant/Contract Number:  
[AC05-00OR22725]
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
[ Journal Volume: 9; Journal Issue: 1]; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Lee, Byoung-Cheol, Khelashvili, George, Falzone, Maria, Menon, Anant K., Weinstein, Harel, and Accardi, Alessio. Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase. United States: N. p., 2018. Web. doi:10.1038/s41467-018-05724-1.
Lee, Byoung-Cheol, Khelashvili, George, Falzone, Maria, Menon, Anant K., Weinstein, Harel, & Accardi, Alessio. Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase. United States. doi:10.1038/s41467-018-05724-1.
Lee, Byoung-Cheol, Khelashvili, George, Falzone, Maria, Menon, Anant K., Weinstein, Harel, and Accardi, Alessio. Tue . "Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase". United States. doi:10.1038/s41467-018-05724-1. https://www.osti.gov/servlets/purl/1565677.
@article{osti_1565677,
title = {Gating mechanism of the extracellular entry to the lipid pathway in a TMEM16 scramblase},
author = {Lee, Byoung-Cheol and Khelashvili, George and Falzone, Maria and Menon, Anant K. and Weinstein, Harel and Accardi, Alessio},
abstractNote = {Members of the TMEM16/ANO family of membrane proteins are Ca2+-activated phospholipid scramblases and/or Cl- channels. A membrane-exposed hydrophilic groove in these proteins serves as a shared translocation pathway for ions and lipids. However, the mechanism by which lipids gain access to and permeate through the groove remains poorly understood. Here, we combine quantitative scrambling assays and molecular dynamic simulations to identify the key steps regulating lipid movement through the groove. Lipid scrambling is limited by two constrictions defined by evolutionarily conserved charged and polar residues, one extracellular and the other near the membrane mid-point. The region between these constrictions is inaccessible to lipids and water molecules, suggesting that the groove is in a non-conductive conformation. A sequence of lipid-triggered reorganizations of interactions between these residues and the permeating lipids propagates from the extracellular entryway to the central constriction, allowing the groove to open and coordinate the headgroups of transiting lipids.},
doi = {10.1038/s41467-018-05724-1},
journal = {Nature Communications},
number = [1],
volume = [9],
place = {United States},
year = {2018},
month = {8}
}

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Cited by: 21 works
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