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

Mattia Malvezzi, Madhavan Chalat, Radmila Janjusevic, Alessandra Picollo, Hiroyuki Terashima, Anant K. Menon and Alessio Accardi ()
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Mattia Malvezzi: Weill Cornell Medical College
Madhavan Chalat: Weill Cornell Medical College
Radmila Janjusevic: Weill Cornell Medical College
Alessandra Picollo: Weill Cornell Medical College
Hiroyuki Terashima: Weill Cornell Medical College
Anant K. Menon: Weill Cornell Medical College
Alessio Accardi: Weill Cornell Medical College

Nature Communications, 2013, vol. 4, issue 1, 1-9

Abstract: 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 Ca2+-gated channels have been shown to be involved in Ca2+-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 Ca2+-gated channel, with characteristics of other TMEM16 homologues, and a Ca2+-dependent scramblase, with the expected properties of mammalian PL scramblases. Remarkably, we find that a single Ca2+ 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.

Date: 2013
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DOI: 10.1038/ncomms3367

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