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The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K

Author

Listed:
  • Simon R. Bushell

    (University of Oxford)

  • Ashley C. W. Pike

    (University of Oxford)

  • Maria E. Falzone

    (Weill Cornell Medical School)

  • Nils J. G. Rorsman

    (University of Oxford
    OxSyBio)

  • Chau M. Ta

    (University of Oxford
    Washington University in St. Louis)

  • Robin A. Corey

    (University of Oxford)

  • Thomas D. Newport

    (University of Oxford
    Oxford Nanopore Technologies)

  • John C. Christianson

    (University of Oxford)

  • Lara F. Scofano

    (University of Oxford)

  • Chitra A. Shintre

    (University of Oxford
    Vertex Pharmaceuticals Ltd)

  • Annamaria Tessitore

    (University of Oxford
    Oxford University)

  • Amy Chu

    (University of Oxford
    Oxford University)

  • Qinrui Wang

    (University of Oxford
    University of Oxford)

  • Leela Shrestha

    (University of Oxford)

  • Shubhashish M. M. Mukhopadhyay

    (University of Oxford)

  • James D. Love

    (Albert Einstein College of Medicine
    Novo Nordisk A/S)

  • Nicola A. Burgess-Brown

    (University of Oxford)

  • Rebecca Sitsapesan

    (University of Oxford)

  • Phillip J. Stansfeld

    (University of Oxford)

  • Juha T. Huiskonen

    (University of Oxford)

  • Paolo Tammaro

    (University of Oxford)

  • Alessio Accardi

    (Weill Cornell Medical School
    Weill Cornell Medical School
    Weill Cornell Medical School)

  • Elisabeth P. Carpenter

    (University of Oxford)

Abstract

Membranes in cells have defined distributions of lipids in each leaflet, controlled by lipid scramblases and flip/floppases. However, for some intracellular membranes such as the endoplasmic reticulum (ER) the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase or chloride channel activity. Although TMEM16K is widely distributed and associated with the neurological disorder autosomal recessive spinocerebellar ataxia type 10 (SCAR10), its location in cells, function and structure are largely uncharacterised. Here we show that TMEM16K is an ER-resident lipid scramblase with a requirement for short chain lipids and calcium for robust activity. Crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional cryo-EM structures reveal extensive conformational changes from the cytoplasmic to the ER side of the membrane, giving a state with a closed lipid permeation pathway. Molecular dynamics simulations showed that the open-groove conformation is necessary for scramblase activity.

Suggested Citation

  • Simon R. Bushell & Ashley C. W. Pike & Maria E. Falzone & Nils J. G. Rorsman & Chau M. Ta & Robin A. Corey & Thomas D. Newport & John C. Christianson & Lara F. Scofano & Chitra A. Shintre & Annamaria , 2019. "The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-11753-1
    DOI: 10.1038/s41467-019-11753-1
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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. 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.
    4. Mingfeng Zhang & Yuanyue Shan & Charles D. Cox & Duanqing Pei, 2023. "A mechanical-coupling mechanism in OSCA/TMEM63 channel mechanosensitivity," Nature Communications, Nature, vol. 14(1), pages 1-9, December.
    5. Shengjie Feng & Cristina Puchades & Juyeon Ko & Hao Wu & Yifei Chen & Eric E. Figueroa & Shuo Gu & Tina W. Han & Brandon Ho & Tong Cheng & Junrui Li & Brian Shoichet & Yuh Nung Jan & Yifan Cheng & Lil, 2023. "Identification of a drug binding pocket in TMEM16F calcium-activated ion channel and lipid scramblase," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    6. Samuel Hume & Claudia P. Grou & Pauline Lascaux & Vincenzo D’Angiolella & Arnaud J. Legrand & Kristijan Ramadan & Grigory L. Dianov, 2021. "The NUCKS1-SKP2-p21/p27 axis controls S phase entry," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    7. 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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