TY - JOUR T1 - The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K JF - bioRxiv DO - 10.1101/447417 SP - 447417 AU - Simon R. Bushell AU - Ashley C.W. Pike AU - Maria E. Falzone AU - Nils J. G. Rorsman AU - Chau M Ta AU - Robin A. Corey AU - Thomas D. Newport AU - Chitra A. Shintre AU - Annamaria Tessitore AU - Amy Chu AU - Qinrui Wang AU - Leela Shrestha AU - Shubhashish M.M. Mukhopadhyay AU - James D. Love AU - Nicola A. Burgess-Brown AU - Rebecca Sitsapesan AU - Phillip J. Stansfeld AU - Juha T. Huiskonen AU - Paolo Tammaro AU - Alessio Accardi AU - Elisabeth P. Carpenter Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/10/19/447417.abstract N2 - 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 the scramblases have not been identified. Members of the TMEM16 family have either lipid scramblase and ion channel activity, or specific 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 calcium-regulated lipid scramblase. Our crystal structures of TMEM16K show a scramblase fold, with an open lipid transporting groove. Additional structures solved by cryo-EM reveal extensive conformational changes extending 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. Our results suggest mechanisms by which missense variants of TMEM16K could cause SCAR10 ataxia, providing new hypotheses to explore for therapy. ER -