title: Ca2+-dependent phospholipid scrambling by a reconstituted TMEM16 ion channel.
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.
authors.affiliation: Department of Anesthesiology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Mattia
authors.initials: M
authors.lastname: Malvezzi
authors.forename: Madhavan
authors.initials: M
authors.lastname: Chalat
authors.forename: Radmila
authors.initials: R
authors.lastname: Janjusevic
authors.forename: Alessandra
authors.initials: A
authors.lastname: Picollo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Terashima
authors.forename: Anant K
authors.initials: AK
authors.lastname: Menon
authors.forename: Alessio
authors.initials: A
authors.lastname: Accardi
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus / Q000378:metabolism*; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism; D005656:Fungal Proteins / Q000302:isolation & purification / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating; D017136:Ion Transport; D007477:Ions; D050356:Lipid Metabolism; D008322:Mammals / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000378:metabolism*; D010743:Phospholipids / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D002712:Chlorides; D005656:Fungal Proteins; D007477:Ions; D049294:Phospholipid Transfer Proteins; D010743:Phospholipids; D002118:Calcium