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

Khelashvili, George; Kots, Ekaterina; Cheng, Xiaolu; Levine, Michael V.; Weinstein, Harel

doi:10.1038/s42003-022-03930-8

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

Journal Article · Mon Sep 19 00:00:00 EDT 2022 · Communications Biology

DOI:https://doi.org/10.1038/s42003-022-03930-8· OSTI ID:1982177

^[1]; Kots, Ekaterina ^[1]; Cheng, Xiaolu ^[1]; Levine, Michael V. ^[1];

^[1]

Weill Cornell Medicine, New York, NY (United States)

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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); National Institutes of Health (NIH)

Grant/Contract Number:: AC05-00OR22725; R01GM106717

OSTI ID:: 1982177

Journal Information:: Communications Biology, Vol. 5, Issue 1; ISSN 2399-3642

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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

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