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

DOI: 10.1038/s41467-019-11753-1 DOI Help

Authors: Simon R. Bushell (Structural Genomics Consortium, University of Oxford) , Ashley C. W. Pike (Structural Genomics Consortium, 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 Shintre (Structural Genomics Consortium, University of Oxford) , Annamaria Tessitore (Structural Genomics Consortium, University of Oxford) , Amy Chu (Structural Genomics Consortium, University of Oxford) , Qinrui Wang (Structural Genomics Consortium, 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 (Structural Genomics Consortium, University of Oxford) , Rebecca Sitsapesan (University of Oxford) , Phillip J. Stansfeld (University of Oxford) , Juha T. Huiskonen (Wellcome Centre for Human Genetics, University of Oxford) , Paolo Tammaro (University of Oxford) , Alessio Accardi (Weill Cornell Medical School) , Elisabeth P. Carpenter (Structural Genomics Consortium, University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 10

State: Published (Approved)
Published: September 2019
Diamond Proposal Number(s): 10619 , 15433

Open Access Open Access

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.

Journal Keywords: Electron microscopy; Lipids; X-ray crystallography

Subject Areas: Biology and Bio-materials

Instruments: I24-Microfocus Macromolecular Crystallography