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

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Bushell, Simon R., Pike, Ashley C. W., Falzone, Maria E., Rorsman, Nils J. G., Ta, Chau M., Corey, Robin A., Newport, Thomas D., Christianson, John C., Scofano, Lara F., Shintre, Chitra A. et al.
(2019) The structural basis of lipid scrambling and inactivation in the endoplasmic reticulum scramblase TMEM16K. Nature Communications, 10 (1). 3956 . doi:10.1038/s41467-019-11753-1

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Official URL: http://dx.doi.org/10.1038/s41467-019-11753-1

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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.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Library of Congress Subject Headings (LCSH): Lipids , Membrane lipids, Cell membranes, Biological transport, Endoplasmic reticulum
Journal or Publication Title: Nature Communications
Publisher: Nature Publishing Group
ISSN: 2041-1723
Official Date: 2 September 2019
Dates:
DateEvent
2 September 2019Published
Volume: 10
Number: 1
Article Number: 3956
DOI: 10.1038/s41467-019-11753-1
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
106169/Z/14/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
OXION grant no: WT084655MAWellcome Trusthttp://dx.doi.org/10.13039/100010269
UNSPECIFIEDBritish Heart Foundationhttp://dx.doi.org/10.13039/501100000274
208361/Z/17/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
BB/ P01948X/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
BB/I019855/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
Doctoral Training Centre studentship[EPSRC] Engineering and Physical Sciences Research Councilhttp://dx.doi.org/10.13039/501100000266

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