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An inner activation gate controls TMEM16F phospholipid scrambling

Author

Listed:
  • Trieu Le

    (Duke University Medical Center)

  • Zhiguang Jia

    (University of Massachusetts)

  • Son C. Le

    (Duke University Medical Center)

  • Yang Zhang

    (Duke University Medical Center)

  • Jianhan Chen

    (University of Massachusetts
    University of Massachusetts)

  • Huanghe Yang

    (Duke University Medical Center
    Duke University Medical Center)

Abstract

Transmembrane protein 16F (TMEM16F) is an enigmatic Ca2+-activated phospholipid scramblase (CaPLSase) that passively transports phospholipids down their chemical gradients and mediates blood coagulation, bone development and viral infection. Despite recent advances in the structure and function understanding of TMEM16 proteins, how mammalian TMEM16 CaPLSases open and close, or gate their phospholipid permeation pathways remains unclear. Here we identify an inner activation gate, which is established by three hydrophobic residues, F518, Y563 and I612, in the middle of the phospholipid permeation pathway of TMEM16F-CaPLSase. Disrupting the inner gate profoundly alters TMEM16F phospholipid permeation. Lysine substitutions of F518 and Y563 even lead to constitutively active CaPLSases that bypass Ca2+-dependent activation. Strikingly, an analogous lysine mutation to TMEM16F-F518 in TMEM16A (L543K) is sufficient to confer CaPLSase activity to the Ca2+-activated Cl− channel (CaCC). The identification of an inner activation gate can help elucidate the gating and permeation mechanism of TMEM16 CaPLSases and channels.

Suggested Citation

  • Trieu Le & Zhiguang Jia & Son C. Le & Yang Zhang & Jianhan Chen & Huanghe Yang, 2019. "An inner activation gate controls TMEM16F phospholipid scrambling," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09778-7
    DOI: 10.1038/s41467-019-09778-7
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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. Susan A. Leonhardt & Michael D. Purdy & Jonathan R. Grover & Ziwei Yang & Sandra Poulos & William E. McIntire & Elizabeth A. Tatham & Satchal K. Erramilli & Kamil Nosol & Kin Kui Lai & Shilei Ding & M, 2023. "Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. 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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