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Membrane lipids are both the substrates and a mechanistically responsive environment of TMEM16 scramblase proteins.

TitleMembrane lipids are both the substrates and a mechanistically responsive environment of TMEM16 scramblase proteins.
Publication TypeJournal Article
Year of Publication2020
AuthorsKhelashvili G, Cheng X, Falzone ME, Doktorova M, Accardi A, Weinstein H
JournalJ Comput Chem
Volume41
Issue6
Pagination538-551
Date Published2020 Mar 05
ISSN1096-987X
Abstract

Recent discoveries about functional mechanisms of proteins in the TMEM16 family of phospholipid scramblases have illuminated the dual role of the membrane as both the substrate and a mechanistically responsive environment in the wide range of physiological processes and genetic disorders in which they are implicated. This is highlighted in the review of recent findings from our collaborative investigations of molecular mechanisms of TMEM16 scramblases that emerged from iterative functional, structural, and computational experimentation. In the context of this review, we present new MD simulations and trajectory analyses motivated by the fact that new structural information about the TMEM16 scramblases is emerging from cryo-EM determinations in lipid nanodiscs. Because the functional environment of these proteins in in vivo and in in vitro is closer to flat membranes, we studied comparatively the responses of the membrane to the TMEM16 proteins in flat membranes and nanodiscs. We find that bilayer shapes in the nanodiscs are very different from those observed in the flat membrane systems, but the function-related slanting of the membrane observed at the nhTMEM16 boundary with the protein is similar in the nanodiscs and in the flat bilayers. This changes, however, in the bilayer composed of longer-tail lipids, which is thicker near the phospholipid translocation pathway, which may reflect an enhanced tendency of the long tails to penetrate the pathway and create, as shown previously, a nonconductive environment. These findings support the correspondence between the mechanistic involvement of the lipid environment in the flat membranes, and the nanodiscs. © 2019 Wiley Periodicals, Inc.

DOI10.1002/jcc.26105
Alternate JournalJ Comput Chem
PubMed ID31750558
PubMed Central IDPMC7261202
Grant ListR01GM106717 / / NIH NIGMS /
/ NH / NIH HHS / United States
2019 / / 1923 Fund /
R01 GM116961 / GM / NIGMS NIH HHS / United States
ACI-1053575 / / National Science Foundation /
/ / Office of Science of the U.S. Department of Energy /
/ / Oak Ridge National Laboratory /
R01 GM106717 / GM / NIGMS NIH HHS / United States