Department of Anesthesiology

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Ca2+-dependent phospholipid scrambling by a reconstituted TMEM16 ion channel.

TitleCa2+-dependent phospholipid scrambling by a reconstituted TMEM16 ion channel.
Publication TypeJournal Article
Year of Publication2013
AuthorsMalvezzi M, Chalat M, Janjusevic R, Picollo A, Terashima H, Menon AK, Accardi A
JournalNat Commun
Volume4
Pagination2367
Date Published2013
ISSN2041-1723
Abstract

Phospholipid (PL) scramblases disrupt the lipid asymmetry of the plasma membrane, externalizing phosphatidylserine to trigger blood coagulation and mark apoptotic cells. Recently, members of the TMEM16 family of Ca(2+)-gated channels have been shown to be involved in Ca(2+)-dependent scrambling. It is however controversial whether they are scramblases or channels regulating scrambling. Here we show that purified afTMEM16, from Aspergillus fumigatus, is a dual-function protein: it is a Ca(2+)-gated channel, with characteristics of other TMEM16 homologues, and a Ca(2+)-dependent scramblase, with the expected properties of mammalian PL scramblases. Remarkably, we find that a single Ca(2+) site regulates separate transmembrane pathways for ions and lipids. Two other purified TMEM16-channel homologues do not mediate scrambling, suggesting that the family diverged into channels and channel/scramblases. We propose that the spatial separation of the ion and lipid pathways underlies the evolutionary divergence of the TMEM16 family, and that other homologues, such as TMEM16F, might also be dual-function channel/scramblases.

DOI10.1038/ncomms3367
Alternate JournalNat Commun
PubMed ID23996062
Grant ListGM071041 / GM / NIGMS NIH HHS / United States
GM071041-07S1 / GM / NIGMS NIH HHS / United States
GM085232 / GM / NIGMS NIH HHS / United States