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

TMEM16F is a Ca 2+ -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 c...

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Bibliographic Details
Published in:Communications biology 2022-09, Vol.5 (1), p.990-13, Article 990
Main Authors: Khelashvili, George, Kots, Ekaterina, Cheng, Xiaolu, Levine, Michael V., Weinstein, Harel
Format: Article
Language:English
Subjects:
631/535/1267
631/57/2266
Allosteric properties
Anoctamins - chemistry
Anoctamins - genetics
Anoctamins - metabolism
BASIC BIOLOGICAL SCIENCES
Biology
Biomedical and Life Sciences
Cell Membrane - metabolism
Computational biophysics
Electric Conductivity
Life Sciences
Life Sciences & Biomedicine - Other Topics
Lipids
Membrane proteins
Molecular modelling
Phospholipid Transfer Proteins - genetics
Phospholipid Transfer Proteins - metabolism
Phospholipids
Phospholipids - metabolism
Science & Technology - Other Topics
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Summary:TMEM16F is a Ca 2+ -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 Ca 2+ 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. Molecular dynamics simulations reveal the allosteric mechanism leading to an open, lipid scrambling competent state of a mammalian TMEM16F.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-022-03930-8