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Title: The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase

Abstract

TMEM16F is a Ca2+-activated phospholipid scramblase in the TMEM16 family of membrane proteins. Unlike other TMEM16s exhibiting a membrane-exposed hydrophilic groove that serves as a translocation pathway for lipids, the experimentally determined structures of TMEM16F shows the groove in a closed conformation even under conditions of maximal scramblase activity. It is currently unknown if/how TMEM16F groove can open for lipid scrambling. Here we describe the analysis of ~400 µs all-atom molecular dynamics (MD) simulations of the TMEM16F revealing an allosteric mechanism leading to an open-groove, lipid scrambling competent state of the protein. The groove opens into a continuous hydrophilic conduit that is highly similar in structure to that seen in other activated scramblases. The allosteric pathway connects this opening to an observed destabilization of the Ca2+ ion bound at the distal site near the dimer interface, to the dynamics of specific protein regions that produces the open-groove state to scramble phospholipids.

Authors:
ORCiD logo [1];  [1];  [1];  [1]; ORCiD logo [1]
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  1. Weill Cornell Medicine, New York, NY (United States)
Publication Date:
Research Org.:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institutes of Health (NIH)
OSTI Identifier:
1982177
Grant/Contract Number:  
AC05-00OR22725; R01GM106717
Resource Type:
Accepted Manuscript
Journal Name:
Communications Biology
Additional Journal Information:
Journal Volume: 5; Journal Issue: 1; Journal ID: ISSN 2399-3642
Publisher:
Springer Nature
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Life Sciences & Biomedicine - Other Topics; Science & Technology - Other Topics; Computational biophysics; Molecular modelling

Citation Formats

Khelashvili, George, Kots, Ekaterina, Cheng, Xiaolu, Levine, Michael V., and Weinstein, Harel. The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase. United States: N. p., 2022. Web. doi:10.1038/s42003-022-03930-8.
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Khelashvili, George, Kots, Ekaterina, Cheng, Xiaolu, Levine, Michael V., & Weinstein, Harel. The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase. United States. https://doi.org/10.1038/s42003-022-03930-8
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Khelashvili, George, Kots, Ekaterina, Cheng, Xiaolu, Levine, Michael V., and Weinstein, Harel. Mon . "The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase". United States. https://doi.org/10.1038/s42003-022-03930-8. https://www.osti.gov/servlets/purl/1982177.
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@article{osti_1982177,
title = {The allosteric mechanism leading to an open-groove lipid conductive state of the TMEM16F scramblase},
author = {Khelashvili, George and Kots, Ekaterina and Cheng, Xiaolu and Levine, Michael V. and Weinstein, Harel},
abstractNote = {TMEM16F is a Ca2+-activated phospholipid scramblase in the TMEM16 family of membrane proteins. Unlike other TMEM16s exhibiting a membrane-exposed hydrophilic groove that serves as a translocation pathway for lipids, the experimentally determined structures of TMEM16F shows the groove in a closed conformation even under conditions of maximal scramblase activity. It is currently unknown if/how TMEM16F groove can open for lipid scrambling. Here we describe the analysis of ~400 µs all-atom molecular dynamics (MD) simulations of the TMEM16F revealing an allosteric mechanism leading to an open-groove, lipid scrambling competent state of the protein. The groove opens into a continuous hydrophilic conduit that is highly similar in structure to that seen in other activated scramblases. The allosteric pathway connects this opening to an observed destabilization of the Ca2+ ion bound at the distal site near the dimer interface, to the dynamics of specific protein regions that produces the open-groove state to scramble phospholipids.},
doi = {10.1038/s42003-022-03930-8},
journal = {Communications Biology},
number = 1,
volume = 5,
place = {United States},
year = {Mon Sep 19 00:00:00 EDT 2022},
month = {Mon Sep 19 00:00:00 EDT 2022}
}
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https://doi.org/10.1038/s42003-022-03930-8
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