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

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 Tessitore, Amy Chu, Qinrui Wang, Leela Shrestha, Shubhashish M. M. Mukhopadhyay, James D. Love, Nicola A. Burgess-Brown, Rebecca Sitsapesan, Phillip J. Stansfeld, Juha T. Huiskonen, Paolo Tammaro, Alessio Accardi and Elisabeth P. Carpenter ()
Additional contact information
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
Chau M. Ta: University of Oxford
Robin A. Corey: University of Oxford
Thomas D. Newport: University of Oxford
John C. Christianson: University of Oxford
Lara F. Scofano: University of Oxford
Chitra A. Shintre: University of Oxford
Annamaria Tessitore: University of Oxford
Amy Chu: University of Oxford
Qinrui Wang: University of Oxford
Leela Shrestha: University of Oxford
Shubhashish M. M. Mukhopadhyay: University of Oxford
James D. Love: Albert Einstein College of Medicine
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
Elisabeth P. Carpenter: University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11753-1

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