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X-ray structure of a calcium-activated TMEM16 lipid scramblase

Author

Listed:
  • Janine D. Brunner

    (University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland)

  • Novandy K. Lim

    (University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland)

  • Stephan Schenck

    (University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland)

  • Alessia Duerst

    (University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland)

  • Raimund Dutzler

    (University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland)

Abstract

The TMEM16 family of proteins, also known as anoctamins, features a remarkable functional diversity. This family contains the long sought-after Ca2+-activated chloride channels as well as lipid scramblases and cation channels. Here we present the crystal structure of a TMEM16 family member from the fungus Nectria haematococca that operates as a Ca2+-activated lipid scramblase. Each subunit of the homodimeric protein contains ten transmembrane helices and a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbours a conserved Ca2+-binding site located within the hydrophobic core of the membrane. Mutations of residues involved in Ca2+ coordination affect both lipid scrambling in N. haematococca TMEM16 and ion conduction in the Cl− channel TMEM16A. The structure reveals the general architecture of the family and its mode of Ca2+ activation. It also provides insight into potential scrambling mechanisms and serves as a framework to unravel the conduction of ions in certain TMEM16 proteins.

Suggested Citation

  • Janine D. Brunner & Novandy K. Lim & Stephan Schenck & Alessia Duerst & Raimund Dutzler, 2014. "X-ray structure of a calcium-activated TMEM16 lipid scramblase," Nature, Nature, vol. 516(7530), pages 207-212, December.
    • Handle: RePEc:nat:nature:v:516:y:2014:i:7530:d:10.1038_nature13984
    DOI: 10.1038/nature13984
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    Citations

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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. Lorena Ilcu & Lukas Denkhaus & Anton Brausemann & Lin Zhang & Oliver Einsle, 2023. "Architecture of the Heme-translocating CcmABCD/E complex required for Cytochrome c maturation," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    3. 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.
    4. Shana Bergman & Rosemary J. Cater & Ambrose Plante & Filippo Mancia & George Khelashvili, 2023. "Substrate binding-induced conformational transitions in the omega-3 fatty acid transporter MFSD2A," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Panpan Zhang & Masahiro Maruoka & Ryo Suzuki & Hikaru Katani & Yu Dou & Daniel M. Packwood & Hidetaka Kosako & Motomu Tanaka & Jun Suzuki, 2023. "Extracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    6. 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.
    7. Han Niu & Masahiro Maruoka & Yuki Noguchi & Hidetaka Kosako & Jun Suzuki, 2024. "Phospholipid scrambling induced by an ion channel/metabolite transporter complex," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Elisabeth Lambert & Ahmad Reza Mehdipour & Alexander Schmidt & Gerhard Hummer & Camilo Perez, 2022. "Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    9. Zhongjie Ye & Nicola Galvanetto & Leonardo Puppulin & Simone Pifferi & Holger Flechsig & Melanie Arndt & Cesar Adolfo Sánchez Triviño & Michael Palma & Shifeng Guo & Horst Vogel & Anna Menini & Clemen, 2024. "Structural heterogeneity of the ion and lipid channel TMEM16F," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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