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

Author

Listed:
  • Mattia Malvezzi

    (Weill Cornell Medical College
    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
    Present address: Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan)

  • Anant K. Menon

    (Weill Cornell Medical College)

  • Alessio Accardi

    (Weill Cornell Medical College
    Weill Cornell Medical College
    Weill Cornell Medical College)

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.

Suggested Citation

  • Mattia Malvezzi & Madhavan Chalat & Radmila Janjusevic & Alessandra Picollo & Hiroyuki Terashima & Anant K. Menon & Alessio Accardi, 2013. "Ca2+-dependent phospholipid scrambling by a reconstituted TMEM16 ion channel," Nature Communications, Nature, vol. 4(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3367
    DOI: 10.1038/ncomms3367
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    Cited by:

    1. Melanie Arndt & Carolina Alvadia & Monique S. Straub & Vanessa Clerico Mosina & Cristina Paulino & Raimund Dutzler, 2022. "Structural basis for the activation of the lipid scramblase TMEM16F," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Maria E. Falzone & Zhang Feng & Omar E. Alvarenga & Yangang Pan & ByoungCheol Lee & Xiaolu Cheng & Eva Fortea & Simon Scheuring & Alessio Accardi, 2022. "TMEM16 scramblases thin the membrane to enable lipid scrambling," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Andy K. M. Lam & Sonja Rutz & Raimund Dutzler, 2022. "Inhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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